11

Abstract: In 2020, female breast cancer overtook lung cancer to become the most diagnosed cancer worldwide. Nearly 30% of women diagnosed with early-stage breast cancer have recurrent disease with resistance to therapeutics evidenced in 25% of cases. The hormone receptor positive (ER+ and PR+) and HER2+ breast cancers quickly develop resistance to the frontline therapeutics, namely, endocrine therapy and trastuzumab treatment. The overactivity of the PI3K/mTOR/S6K1 pathway has been shown to lead to multidrug resistant breast cancer. While PI3K and mTOR targeted therapeutics have shown promise, development of resistance and mutations in these proteins have limited the success of these agents. S6K1 kinase, a downstream effector whose activation leads to translation of ribosomal proteins, enhancement of mRNA biogenesis, and cap-dependent translation and elongation, is a critical player in the PI3K/mTOR pathway and the ER+ pathway. Inhibiting the activity of S6K1 can provide the needed therapeutic option for resistant/refractory breast cancer patients.

Keywords: human epidermal growth factor receptor 2; mammalian target of rapamycin; refractory breast cancer; ribosomal protein S6 kinase 1; RPS6K1

INTRODUCTION

The ribosomal protein S6 kinase beta family of genes RPS6KB1 and RPS6KB2 encode several proteins that are serine threonine kinases (1). Alternate use mRNA translational AUG start codons on RPS6KB1 is known to generate distinct isoforms of the protein: p70S6K1, p85S6K1, (2, 3), p60S6K1, and p31S6K1 (4, 5). p85S6K1, the larger isoform, includes the nuclear localization sequence (NLS) in the N-terminus with a 23 amino acid extension which was initially thought to be constitutively nuclear (5–7) but recent studies based on nuclear-cytoplasmic fractionation show its presence in the cytoplasm of breast cancer cells (5, 8). p70S6K1 is thought to be mostly localized in the cytoplasm but studies have shown it to accumulate in the nucleus leading to the conclusion that p70S6K1 may transit between the cytoplasm and nucleus of the cell (5, 9). The scant literature on the shorter isoform p31S6K1 only indicate it to be located in the nuclei of human normal fibroblasts (8). Through phosphorylation, dephosphorylation, ubiquitination and acetylation, S6K1 is involved in protein synthesis, cellular growth, metabolism, cell structure and organization, aging and adiposity, memory, immunity, and muscle hypertrophy (3). Two isoforms, p70S6K1 and p85S6K1, have been extensively studied as these are the targets for mammalian target of rapamycin (mTOR) phosphorylation and play an important role in cancer progression, enhanced cell viability, migration, and resistance to existing therapeutics (10).

S6K1 STRUCTURE AND REGULATION

S6K1 isoforms belong to the AGC serine/threonine protein kinase family. The shorter isoform p70S6K1 has 502 residues and the longer isoform p85S6K1 has 525 residues with the additional NLS 23 residues in the N-terminus. The kinase domains of both isoforms have identical sequences. Eight phosphorylation sites (residue numbers based on p70S6K1 sequence) have been identified in the catalytic domain (Thr229), linker region (Ser371, Thr389 and Ser404), and the putative autoinhibitory region (Ser411, Ser418, Thr421 and Ser424) (11–13) as shown in Figure 1A. The four residues in the autoinhibitory region need to be phosphorylated initially to expose the residues in the catalytic domain and the linker region for phosphorylation. PDK1 phosphorylates Thr229 on S6K1 which is in the activation loop of the kinase domain. Thr389 which is in the hydrophobic motif is the target for mTOR phosphorylation. Both of these phosphorylations are essential for the catalytic activation of the kinase (12). It has been proposed that in the autoinhibitory inactive state, the C-terminus pseudosubstrate domain of S6K1, which is basic in nature, interacts with the N-terminus, which is acidic, and blocks the key phosphorylation sites in the kinase domain (14). Initiation of activation is facilitated by a calcium-dependent priming step (15), followed by sequential phosphorylation of the C-terminus residues (Ser411, Ser418, Thr421 and Ser424) (16) inducing a conformational change opening up the phosphorylation sites on the T-loop, the turn motif, and hydrophobic motif. Phosphorylated T-loop induces critical conformational change to the active form of S6K1. Phosphorylated turn motif stabilizes the phosphorylated hydrophobic motif that binds to the N-lobe hydrophobic pocket (17, 18). The active conformation of the kinase domain bound to an inhibitor 1-(9H-purin-6-yl)-N-[3-(trifluoromethyl)phenyl]piperidine-4-carboxamide is shown in Figure 1B. The molecular surface map depicting the hydrophobic and lipophilic parts of the ATP-binding site (inhibitor replacing ATP) is shown in Figure 1C.

Figure 1. p70 S6K1 structure and schematic overview of S6K1 activating phosphorylation sites. A, p70S6K1 isoform, structure, and domain organization with phosphorylation sites. Residues phosphorylated by 3-phosphoinositide-dependent kinase 1 (PDK1) (Thr229) and mammalian target of rapamycin (mTORC1) (Thr389) are identified. B, The ribbon model of the kinase domain of S6K1 bound to the ligand 1-(9H-purin-6-yl)-N-[3-(trifluoromethyl)phenyl]piperidine-4-carboxamide adapted from reported crystal structure ‘3WF7.pdb’. C, Molecular surface depiction of the ligand binding pocket (3WF7.pdb) colored by lipophilicity (green) and hydrophilicity (purple) and the residues lining the pocket labeled in black.

S6K1 AND BREAST CANCER

Breast cancer is the most prevalent cancer worldwide with 2.3 million new diagnosis and 685,000 deaths globally in 2020. In the United States, the estimated number of new breast cancer diagnosis is 281,550 with 43,600 deaths in the year 2021. There are four main types of breast cancer: luminal A (estrogen receptor [ER] and progesterone receptor [PR- positive status and corresponding human epidermal growth factor receptor 2 [HER2]-negative status); luminal B (ER, PR, and HER2-positive status); HER2-enriched (HER2+) with ER and PR-negative status; and the triple-negative (ER, PR and HER2-negative status). Triple-negative breast cancer has the worst prognosis followed by the HER2+, luminal B, and luminal A. Luminal A is low-grade and has the best prognosis. The PI3K/AKT/mTOR pathway has a major role in cell metabolism, cell growth, cell proliferation, apoptosis and angiogenesis (19). This pathway is one of the most mutated pathways leading to altered protein functions and aberrant phosphorylation (Figure 2) (20, 21). Activation of mTOR is the hallmark of several cancers including breast cancer where it is highly deregulated and plays a key role on tumorigenesis (22). mTOR can associate with either Raptor or Rictor to form two distinct complexes mTORC1 or mTORC2 (23–25). Activated mTORC1 phosphorylates the key substrates p70S6K1 and elongation initiation factor (EIF)-4E binding protein 1 (4EBP1). Activated p70S6K1 promotes ribosome biogenesis and the translation of cell growth and cell division proteins including IRS1, CREMt, ERa, SKAR, FMRP, S6, BAD, GSK3, p21 and Cyclin D1 (26–32). mTORC1 is the downstream regulator of the PI3K/AKT signaling pathway which is activated in 60% of breast cancers (33–35). PI3K pathway indirectly activates mTORC1 mainly through AKT. Phosphorylation of tuberous sclerosis complex 2 (TSC2) by AKT results in its dissociation from TSC1/2 which is a negative regulator of mTORC1 activator RHEB. Additionally, AKT phosphorylates PRAS40 that is associated with Raptor and is an inhibitor of mTORC1 leading to dissociation of Raptor resulting in mTORC1 activation. ERK and RSK in the Ras-MAPK signaling pathway can also phosphorylate TSC2 which then initiates RHEB-mediated activation of mTORC1 (36). Other triggers for mTORC1 activation are intracellular ATP, glucose, and certain amino acids (leucine, arginine, and glutamine) (37).

Figure 2. S6K1 is activated by coordinated phosphorylation by mTORC1 and PDK1. Growth factors, mitogens, and amino acids activate S6K1 through the PI3K/AKT/mTORC1, MAPK, IRS pathways. Activated S6K1 regulates several cellular processes by phosphorylation of substrates: mRNA processing via S6K1 Aly/REF-like target (SKAR), nuclear cap-binding protein subunit 1(CBP80); cap-dependent translation initiation via programmed cell death protein 4 (PDCD4) and eukaryotic translation initiation factor 4B (elF4B); translation elongation via eukaryotic elongation factor 2 kinase (eEF2K); protein folding via T-complex protein 1 subunit beta (CCTβ); cell growth/size via ribosomal protein S 6 (rpS6); synaptic plasticity via fragile X mental retardation protein (FMRP); cell survival via glycogen synthase kinase β (GSK3β), Bcl-2-associated death promoter (BAD); transcription via transcription factors estrogen receptor alpha (ERα) and cAMP-responsive element modulator (CREM_T). ERK, extracellular-signal-regulated kinase; GPCR, G-protein coupled receptor; GRB2, growth factor receptor bound protein 2; IGFR, insulin growth factor receptor; IRS1-4, insulin receptor substrate 1–4; MEK, mitogen activated protein kinase kinase; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; RAF, rapidly accelerated fibrosarcoma; Rheb, Ras homolog enriched in brain; RAS, rat sarcoma virus; RTKs, receptor tyrosine kinases; RSK, ribosomal protein S6 kinase; SOS, son of sevenless; TSC1/2, tuberous sclerosis complex ½.

RPS6KB1 gene amplification

The chromosomal region 17q22-17q23 is found to be often amplified in breast cancer (38). High copy number amplification of RPS6KB1 gene (≥3 copies), which is in the 17q23 genomic region, is evidenced in 10.7% of breast cancer while some amount of amplification of the RPS6KB1 gene is also seen in several other types of cancer (4, 38). Immunohistochemical analysis of normal human breast tissue, benign and malign breast tissues have clearly shown that S6K1 is overexpressed in cancerous breast tissues when compared to normal breast tissues (39, 40). A study of 368 patients indicated increased risk of locoregional recurrence in breast cancer with an associated p70S6K1 overexpression and established p70S6K1 as a prognostic marker for locoregional recurrence indicating a key role (41). In a study of the global whole genome mRNA levels of S6K1 overexpressed tumors using the publicly available van de Vijver cohort (n = 295) showed positive association with RPS6 and PI3KCA mRNA in the PI3K/AKT/mTOR pathway (42).

S6K1 and receptor tyrosine kinases in breast cancer

HER2, and epidermal growth factor receptor (EGFR) belong to the ERBB family of receptor tyrosine kinases (RTKs- EGFR, HER2, HER3 and HER4)) that stimulate the PI3K/AKT/mTOR/S6K1 pathways. Overexpression of HER2 is evidenced in 20–30% of breast cancers (43) with the HER2 gene amplification being the main cause. While ligand binding activates EGFR, HER2 does not directly bind to any ligands for activation. Homo- and heterodimerization induce autophosphorylation in the intracellular kinase domain of these receptors (44). HER2-targeted therapies include antibodies that prevent dimerization in the extracellular domains, such as trastuzumab and pertuzumab, and reversible/irreversible ATP-competitive inhibitors of the kinase domain (lapatinib/neratinib) (45). These therapeutics have greatly improved the 5-year survival rates of luminal A/B breast cancer patients. Resistance to these therapeutics develop often with intrinsic HER2 alterations, constitutive activation of downstream PI3K pathway due to the activating mutation of downstream proteins, overexpression other ERBB family members and RTKs such as insulin-growth factor receptor 1 (IGFR1), fibroblast growth factor receptor-4 (FGFR4), and inactivation of tumor suppressor proteins (46–51). About 70% of HER2-positive breast cancer patients develop de novo or acquired resistance to trastuzumab leading to refractory metastatic breast cancer (52, 53). It has been shown that intense trastuzumab treatment induces PDK1 and mTORC1 phosphorylated activation of S6K1 exclusively in trastuzumab resistant breast cancer cells leading to the suggestion that S6K1 can function as an early biomarker of trastuzumab resistance and a viable target for inhibition for the treatment of refractory breast cancer (54).

Triple-negative breast cancers involve several pathways leading to cell division, cell growth, cell migration, and metastasis. The most prominent among these pathways is the EGFR overexpression and activation resulting in increased resistance to conventional therapies (55). It has been shown that anti-EGFR targeted therapies are beneficial for triple-negative breast cancers but have failed to demonstrate significant clinical efficacy as a standalone therapy. This lack of significant efficacy has been attributed to the constitutive activation of PI3K/AKT/mTOR pathway due to other genetic aberrations. A combination therapy approach that co-targets multiple proteins in this pathway may achieve efficient therapeutic effect for triple-negative breast cancer (56). Recent studies on the inhibition of S6K1 with the specific inhibitor PF-4708671 have shown promising potent anti-metastatic effect on triple-negative breast cancer cell lines (57).

FGFR4, a member of the receptor tyrosine kinase (RTK) family, is overexpressed in 30% of breast cancers (58). FGFR in conjunction with HER2 regulates the activity of cyclin D1 through MAPK and AKT/S6K1 pathways (Figure 3). Based on the cell type and nature of the activating RTK, S6K1 stimulation occurs resulting in translational control of cyclin D1. Depletion of S6K1 by siRNA resulted in the reduction of S6 phosphorylation that led to a 20–30% decrease in cyclin D1 levels (59).

Figure 3. Model of regulation of cyclin D1 expression by collaboration between FGFR-4 and HER2 pathways leading to cell proliferation proposed by Koziczak and Hynes (61).

S6K1 and estrogen receptor alpha in breast cancer

Estrogen dependence is evidenced in 60% of breast cancers and targeted therapy with endocrine treatments such as antiestrogens and aromatase inhibitors have been frontline in clinical settings (60). Unfortunately, only 50% of ER+ breast cancers respond to endocrine treatments, and resistance develops eventually (60). The MAPK, PI3K and mTORC1 pathways have been implicated in resistance development in ER+ breast cancer leading to a deeper exploration of close interaction between the mTORC1/S6K1 and ER signaling (61). S6K1 can directly phosphorylate estrogen receptor alpha (ERα) on Ser167 in a ligand independent manner resulting in increased ERα transcriptional activity and enhanced cell proliferation (Figure 4) (62). Furthermore, estrogen induces the overexpression of S6K1 leading to the development and progression of breast cancer (63). The co-stimulatory relationship between ERα and S6K1 was evident in driving cell proliferation in low serum conditions with S6K1 able to partially rescue ERα knockdown (61, 64). Interestingly, S6K1 promoted ERα activation even in the absence of estrogen, leading to stimulation of cell proliferation and tumor transformation (61, 64, 65).

Figure 4. Positive co-regulatory mechanism of S6K1 and ERα. Estrogen binding and phosphorylation by S6K1 activates ERα leading to its dissociation of heat shock proteins (HSPs) and dimerization. ERα dimer translocates to the nucleus where it activates the promoter region of RPS6KB1 and upregulates the transcription of S6K1 mRNA resulting in a positive feed-forward loop.

Estrogen-related receptor alpha (ERRα), an orphan nuclear factor and a master regulator of cellular energy metabolism, is an essential regulator of tumor development as it provides for the energy needs of proliferating tumor cells (66, 67). ERRα expression is significantly increased in triple-negative breast cancer and ERα-negative breast cancers. MDA-MB-231 cells with reduced expression of ERRα showed increased expression levels of S6K1 mRNA and protein levels in conjunction with downregulation of ERα. ERRα was found to negatively regulate S6K1 expression by directly binding to its promoter, and inhibition of ERRα under low serum conditions resulted in increased expression of S6K1 due to increase in RPS6KB1 gene expression (68).

TARGETING S6K1 FOR BREAST CANCER THERAPY

The importance of S6K1 in cell growth, cell proliferation, and metastasis is clearly evident in most types of breast cancers and thus S6K1 inhibition is emerging as a highly potential strategy for resistant/metastatic/refractory breast cancer. Frequent mutations in PI3K and PTEN lead to hyperactivation of mTOR and S6K1 (69, 70). Resistance to mTORC1 therapeutic rapamycin in cancer cells has been attributed to MAPK interacting kinase (MNK) which promoted subcomplex formation between MNK and mTORC1while decreasing the binding of DEPTOR (an mTOR inhibitor) to mTORC1 (71–74). Certain studies have hinted on S6K1 activation occurs by the action of eIF4E which is activated by MNK upon prolonged exposure to rapamycin (75). S6K1 hyperactivation has also been evidenced in breast cancers with mutations in IGF-1R, HER2, and FGFR (76). Additionally, RPS6KB1 gene gain in ER+ breast cancer cells were a predictor of poor prognosis with S6K1 indicated as an important kinase for the growth of long-term estrogen deprived MCF7/LTED cells (77). All of these studies indicate that therapeutic intervention using S6K1 inhibitors can help for breast cancer cells that are resistant to current therapeutics.

In response to the evidenced role of S6K1 in resistant and refractory cancers, pharmaceutical companies have launched drug discovery efforts for S6K1 ATP-competitive inhibitors. Several compounds have been identified as S6K1 inhibitors belonging to the structural classes of indazoles, imidazoles, benzimidazoles, ureas, thiones, phenylpyrazoles, pyrozolopyrimidines, isoindolinones and organometallics (Figure 5).

Figure 5. Structures of reported S6K1 ATP-competitive inhibitors.

PF-4708671

Pfizer developed the first specific S6K1 inhibitor PF-4708671 (IC₅₀ of 0.160 μM), a benzimidazole derivative, along with 77 other protein kinases including 13 AGC kinase family members and its closest homolog S6K2 (IC₅₀ = 65 μM) (78). RSK1, RSK2 and MSK1 were the other kinases inhibited by PF-4708671 (IC₅₀ = 4.7 μM, 9.2 μM and 0.95 μM, respectively). PF-4708671 decreased phosphorylation of ribosomal protein S6 in HEK-293 cells. PF-4708671 has been used as the standard S6K1 inhibitor for the investigation of the role of S6K1 in several cancers. PF-4708671 in combination with tamoxifen was shown to be highly effective against ER+ MCF7 cells that had overexpression of S6K1 (79) and enhanced cell death in glucose-starved MCF7 cells via downregulation of anti-apoptotic proteins Mcl-1 and survivin (80). The inhibitory effect of PF-4708671 on the AKT/mTOR/S6K1 pathway led to the inhibition of cell migration in triple-negative MDA-MB-231 cells and inhibition of local relapse in mice models (57, 81).

FS-115

The structure of the compound FS-115 has not been disclosed. FS-115 is reported to be a specific inhibitor of S6K1 (IC₅₀ = 0.035 μM), S6K2 (IC₅₀ = 2.06 μM), and AKT2 (IC₅₀ = 23.8 μM). FS-115 showed high efficacy in the growth inhibition of the triple-negative MBA-MD-231 cells with good pharmacokinetic and pharmacodynamics profile (82). Initial preclinical trials have indicated FS-115 is well tolerated in breast cancer patients with efficient suppression of distant metastasis formation (82).

LY2584702

Eli Lilly identified a 4-aminopyrazolopyrimidine molecule LY2584702, an inhibitor of p70S6K1, as an anti-tumor agent in advanced solid tumors in phase I and phase II trials (83, 84). LY2584702 was used to study the effect of S6K1 inhbition on non-small cell lung cancer (NSCLC) to establish phosphorylated S6K1 levels as prognostic marker for NSCLC patients. LY2584702 was found to suppress proliferation of NSCLC cells in-vitro (85).

Other heterocycles and urea derivatives

A series of pyrazolopyrimidines developed at Exelixis and derivatives exhibited selectivity for S6K1 (IC₅₀ = 0.002 μM), Rsk2, PKA, AKT1 and AKT2 (IC₅₀ values of 0.068, 0.042, 0.371 and 3.021 μM, respectively). Initial in-vivo xenograft studies on PC3 prostate cancer cell lines showed promising efficacy (86). The active ingredient of the immunosuppressive drug leflunomide, an isoxazole derivative A77 1726, inhibited S6K1 with an IC₅₀ value of 0.080 μM. It was shown that A77 1726 exerted anti-proliferative effects in lymphocytes and tumor cells, and induced autophagy in part by inhibiting S6K1 activity (87). A series of 3-amino-1,2,5-oxadiazole derivatives developed by Vertex pharmaceuticals and Biofocus were found to be potent and selective inhibitors of S6K1. Two of these derivatives the 5-hydroxy-4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine and 5-amino-4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine (derivatives 26 and 27) exhibited <0.001 μM IC50 values with good selectivity over other AGC kinases (88).

Oltipraz belonging to a novel class of 1,2-dithiole-3-thiones were developed as S6K1 inhibitors by Sang Geon Kim’s research group (89). Oltipraz inhibition of S6K1 was in conjunction with a H₂O₂ scavenging effect that resulted in HIF-1α activity inhibition and HIF-1α dependent tumor growth (90). The cancer therapeutic potential of oltipraz was explored extensively in in-vivo studies where oltipraz was found to induce diverse phase 2 enzymes, thereby decreasing the formation of carcinogen-DNA adducts (91). Phase 1 and 2 clinical trials indicated beneficial effects of oltipraz having diverse pharmacologic effects including reduced tumor growth (92). A series of thiophene urea derivatives that were initially identified as p39 inhibitors with an off-target activity against S6K1 were subjected to structure optimization studies that led to the development of a potent S6K1 inhibitor (IC₅₀ = 0.015 μM) with excellent selectivity for S6K1 over 43 other kinases (93). Pharmacokinetic studies on thiophene urea derivatives indicated only moderate bioavailability and microsomal stability (94).

Derivatives of isoindoline-1,3-diones have been patented as S6K1inhibitors by Sridhar research lab (95). Derivatives of the isoindoline-1,3-dione series exhibited specific inhibition of S6K1 (IC₅₀ values of 1–5 μM), WEE1, and PLK3 kinases from a panel of 120 kinases. These compounds inhibited growth of multiple breast cancer cell lines that were ER+, HER2+ and triple-negative. Derivatives of indazoles have been patented by Sanofi-Aventis (96) as S6K1 inhibitors. Specificity and potency information for the indazole derivatives are not yet available. The search for natural products that are S6K1 inhibitors have resulted in the identification of rosmarinic acid methyl ester (RAME) (97) and gingerenone A (Gin A) (98) as S6K1 inhibitors with therapeutic potential for cancer and insulin resistance. RAME fully inhibited S6K1 activity at a concentration of 80 μM. RAME was also shown to induce autophagy and apoptosis in cervical cancer cells (97). Gin A was found to decrease S6 phosphorylation in a dose dependent manner and overcomes insulin resistance and enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes and L6 myotubes (98). Organometallics complexes based on the core structure of staurosporine were developed as S6K1 inhibitors (99). The best complex, FL772, inhibited S6K1 (IC₅₀ = 0.0073 μM) with >65% inhibition of 26 out of 456 kinases. FL772 was only able to inhibit S6 phosphorylation in budding yeast but not in 293T and BRAF^V600E mutant melanoma cells.

CONCLUSION

Over the past two decades, enormous insight has been obtained on the role of S6K1 as regulator of cell growth and proliferation. Targeting S6K1 for therapeutic intervention in resistant and refractory breast cancer is promising. Several pharmaceutical companies and research groups have begun exploring the use of ATP-competitive inhibitors of S6K1 in treatment of cancers. Further studies are still needed to understand the overall function of S6K1 in different types of breast cancer to achieve complete success as therapeutics.

Conflict of Interest: The authors declare no potential conflicts of interest with respect to research, authorship and/or publication of this manuscript.

Copyright and Permission Statement: The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced.

REFERENCES

1. Fenton TR, Gout IT. Functions and regulation of the 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol. 2011;43(1):47–59. https://doi.org/10.1016/j.biocel.2010.09.018
2. Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 2012;441(1):1–21. https://doi.org/10.1042/BJ20110892
3. Tavares MR, Pavan IC, Amaral CL, Meneguello L, Luchessi AD, Simabuco FM. The S6K protein family in health and disease. Life Sci. 2015;131:1–10. https://doi.org/10.1016/j.lfs.2015.03.001
4. Ben-Hur V, Denichenko P, Siegfried Z, Maimon A, Krainer A, Davidson B, et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep. 2013;3(1):103–15. https://doi.org/10.1016/j.celrep.2012.11.020
5. Kim D, Akcakanat A, Singh G, Sharma C, Meric-Bernstam F. Regulation and localization of ribosomal protein S6 kinase 1 isoforms. Growth Factors. 2009;27(1):12–21. https://doi.org/10.1080/08977190802556986
6. Coffer PJ, Woodgett JR. Differential subcellular localisation of two isoforms of p70 S6 protein kinase. Biochem Biophys Res Commun. 1994;198(2):780–6. https://doi.org/10.1006/bbrc.1994.1112
7. Reinhard C, Thomas G, Kozma SC. A single gene encodes two isoforms of the p70 S6 kinase: activation upon mitogenic stimulation. Proc Natl Acad Sci U S A. 1992;89(9):4052–6. https://doi.org/10.1073/pnas.89.9.4052
8. Rosner M, Hengstschlager M. Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2/mTOR. Oncogene. 2011;30(44):4509–22. https://doi.org/10.1038/onc.2011.165
9. Panasyuk G, Nemazanyy I, Zhyvoloup A, Bretner M, Litchfield DW, Filonenko V, et al. Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17. J Biol Chem. 2006;281(42):31188–201. https://doi.org/10.1016/S0021-9258(19)84032-2
10. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017;168(6):960–76. https://doi.org/10.1016/j.cell.2017.02.004
11. Ferrari S, Bannwarth W, Morley SJ, Totty NF, Thomas G. Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs. Proc Natl Acad Sci U S A. 1992;89(15):7282–6. https://doi.org/10.1073/pnas.89.15.7282
12. Moser BA, Dennis PB, Pullen N, Pearson RB, Williamson NA, Wettenhall RE, et al. Dual requirement for a newly identified phosphorylation site in p70s6k. Mol Cell Biol. 1997;17(9):5648–55. https://doi.org/10.1128/MCB.17.9.5648
13. Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, et al. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J. 1995;14(21):5279–87. https://doi.org/10.1002/j.1460-2075.1995.tb00212.x
14. Mukhopadhyay NK, Price DJ, Kyriakis JM, Pelech S, Sanghera J, Avruch J. An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. J Biol Chem. 1992;267(5):3325–35. https://doi.org/10.1016/S0021-9258(19)50735-9
15. Hannan KM, Thomas G, Pearson RB. Activation of S6K1 (p70 ribosomal protein S6 kinase 1) requires an initial calcium-dependent priming event involving formation of a high-molecular-mass signalling complex. Biochem J. 2003;370(Pt 2):469–77. https://doi.org/10.1042/bj20021709
16. Ragan TJ, Ross DB, Keshwani MM, Harris TK. Expression, purification, and characterization of a structurally disordered and functional C-terminal autoinhibitory domain (AID) of the 70 kDa 40S ribosomal protein S6 kinase-1 (S6K1). Protein Expr Purif. 2008;57(2):271–9. https://doi.org/10.1016/j.pep.2007.09.014
17. Jacinto E, Lorberg A. TOR regulation of AGC kinases in yeast and mammals. Biochem J. 2008;410(1):19–37. https://doi.org/10.1042/BJ20071518
18. Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol. 2010;11(1):9–22. https://doi.org/10.1038/nrm2822
19. Lim W, Mayer B, Pawson T. Cell Signaling: Principles and Mechanisms. New York, NY, USA: Garland Science; 2015. https://doi.org/10.1201/9780429258893
20. Sobral-Leite M, Salomon I, Opdam M, Kruger DT, Beelen KJ, van der Noort V, et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019;21(1):90. https://doi.org/10.1186/s13058-019-1176-2
21. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084–91. https://doi.org/10.1158/0008-5472.CAN-07-6854
22. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93. https://doi.org/10.1016/j.cell.2012.03.017
23. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369(6483):756–8. https://doi.org/10.1038/369756a0
24. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8. https://doi.org/10.1038/ncb1183
25. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–302. https://doi.org/10.1016/j.cub.2004.06.054
26. Bahrami BF, Ataie-Kachoie P, Pourgholami MH, Morris DL. p70 Ribosomal protein S6 kinase (Rps6kb1): an update. J Clin Pathol. 2014;67(12):1019–25. https://doi.org/10.1136/jclinpath-2014-202560
27. Peterson RT, Schreiber SL. Translation control: connecting mitogens and the ribosome. Curr Biol. 1998;8(7):R248–50. https://doi.org/10.1016/S0960-9822(98)70152-6
28. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 2004;23(8):1761–9. https://doi.org/10.1038/sj.emboj.7600193
29. Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 1998;17(22):6649–59. https://doi.org/10.1093/emboj/17.22.6649
30. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20(16):4370–9. https://doi.org/10.1093/emboj/20.16.4370
31. Lane HA, Fernandez A, Lamb NJ, Thomas G. p70s6k function is essential for G1 progression. Nature. 1993;363(6425):170–2. https://doi.org/10.1038/363170a0
32. Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, et al. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004;14(17):1540–9. https://doi.org/10.1016/j.cub.2004.08.061
33. Araki K, Miyoshi Y. Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer. 2018;25(4):392–401. https://doi.org/10.1007/s12282-017-0812-x
34. Guerrero-Zotano A, Mayer IA, Arteaga CL. PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev. 2016;35(4):515–24. https://doi.org/10.1007/s10555-016-9637-x
35. Sharma VR, Gupta GK, Sharma AK, Batra N, Sharma DK, Joshi A, et al. PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation. Curr Pharm Des. 2017;23(11):1633–8. https://doi.org/10.2174/1381612823666161116125218
36. Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol. 2008;18(17):1269–77. https://doi.org/10.1016/j.cub.2008.07.078
37. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577–90. https://doi.org/10.1016/S0092-8674(03)00929-2
38. Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, et al. Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. Proc Natl Acad Sci U S A. 2001;98(10):5711–6. https://doi.org/10.1073/pnas.091582298
39. Filonenko VV, Tytarenko R, Azatjan SK, Savinska LO, Gaydar YA, Gout IT, et al. Immunohistochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol. 2004;26(4):294–9.
40. Savinska LO, Lyzogubov VV, Usenko VS, Ovcharenko GV, Gorbenko ON, Rodnin MV, et al. Immunohistochemical analysis of S6K1 and S6K2 expression in human breast tumors. Eksp Onkol. 2004;26(1):24–30.
41. van der Hage JA, van den Broek LJ, Legrand C, Clahsen PC, Bosch CJ, Robanus-Maandag EC, et al. Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients. Br J Cancer. 2004;90(8):1543–50. https://doi.org/10.1038/sj.bjc.6601741
42. Karlsson E, Magic I, Bostner J, Dyrager C, Lysholm F, Hallbeck AL, et al. Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis. PLoS One. 2015;10(12):e0145013. https://doi.org/10.1371/journal.pone.0145013
43. Ross JS, Fletcher JA. The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy. Oncologist. 1998;3(4):237–52. https://doi.org/10.1634/theoncologist.3-4-237
44. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. https://doi.org/10.1038/35052073
45. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25(3):282–303. https://doi.org/10.1016/j.ccr.2014.02.025
46. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402. https://doi.org/10.1016/j.ccr.2007.08.030
47. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–27. https://doi.org/10.1016/j.ccr.2004.06.022
48. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65(23):11118–28. https://doi.org/10.1158/0008-5472.CAN-04-3841
49. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13(16):4909–19. https://doi.org/10.1158/1078-0432.CCR-07-0701
50. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99(8):628–38. https://doi.org/10.1093/jnci/djk134
51. Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol. 2012;2:62. https://doi.org/10.3389/fonc.2012.00062
52. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71(5):1515–9. https://doi.org/10.1158/0008-5472.CAN-10-3795
53. Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, et al. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009;8(8):2152–62. https://doi.org/10.1158/1535-7163.MCT-09-0295
54. Huynh FC, Nguyen D, Jones FE. Trastuzumab stimulation of ribosomal protein S6 kinase 1 (S6K1) predicts de novo trastuzumab resistance. Biochem Biophys Res Commun. 2017;483(1):739–44. https://doi.org/10.1016/j.bbrc.2016.12.072
55. Neophytou C, Boutsikos P, Papageorgis P. Molecular Mechanisms and Emerging Therapeutic Targets of Triple-Negative Breast Cancer Metastasis. Front Oncol. 2018;8:31. https://doi.org/10.3389/fonc.2018.00031
56. El Guerrab A, Bamdad M, Bignon YJ, Penault-Llorca F, Aubel C. Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells. Sci Rep. 2020;10(1):6367. https://doi.org/10.1038/s41598-020-63310-2
57. Khotskaya YB, Goverdhan A, Shen J, Ponz-Sarvise M, Chang SS, Hsu MC, et al. S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer. Am J Transl Res. 2014;6(4):361–76. https://doi.org/10.1158/1557-3125.MODORG-A49
58. Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M, et al. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res. 2002;62(3):840–7.
59. Koziczak M, Hynes NE. Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation. J Biol Chem. 2004;279(48):50004–11. https://doi.org/10.1074/jbc.M404252200
60. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452–61. https://doi.org/10.1200/JCO.2010.34.4879
61. Holz MK. The role of S6K1 in ER-positive breast cancer. Cell Cycle. 2012;11(17):3159–65. https://doi.org/10.4161/cc.21194
62. Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S, et al. Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene. 2012;31(49):5073–80. https://doi.org/10.1038/onc.2011.657
63. Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB, et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature. 2009;462(7269):58–64. https://doi.org/10.1038/nature08497
64. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284(10):6361–9. https://doi.org/10.1074/jbc.M807532200
65. Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett. 2010;584(1):124–8. https://doi.org/10.1016/j.febslet.2009.11.041
66. Jarzabek K, Koda M, Kozlowski L, Sulkowski S, Kottler ML, Wolczynski S. The significance of the expression of ERRalpha as a potential biomarker in breast cancer. J Steroid Biochem Mol Biol. 2009;113(1–2):127–33. https://doi.org/10.1016/j.jsbmb.2008.12.005
67. Stein RA, Chang CY, Kazmin DA, Way J, Schroeder T, Wergin M, et al. Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer. Cancer Res. 2008;68(21):8805–12. https://doi.org/10.1158/0008-5472.CAN-08-1594
68. Deblois G, Giguere V. Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer. 2013;13(1):27–36. https://doi.org/10.1038/nrc3396
69. Fleming GF, Ma CX, Huo D, Sattar H, Tretiakova M, Lin L, et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat. 2012;136(2):355–63. https://doi.org/10.1007/s10549-011-1910-7
70. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87. https://doi.org/10.1200/JCO.2008.20.0766
71. Brown MC, Gromeier M. MNK Controls mTORC1:Substrate Association through Regulation of TELO2 Binding with mTORC1. Cell Rep. 2017;18(6):1444–57. https://doi.org/10.1016/j.celrep.2017.01.023
72. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118(9):3065–74. https://doi.org/10.1172/JCI34739
73. Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T, Sonenberg N. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. EMBO J. 1999;18(1):270–9. https://doi.org/10.1093/emboj/18.1.270
74. Wang X, Yue P, Chan CB, Ye K, Ueda T, Watanabe-Fukunaga R, et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol Cell Biol. 2007;27(21):7405–13. https://doi.org/10.1128/MCB.00760-07
75. Majeed ST, Majeed R, Shah G, Andrabi KI. S6 Kinase: A compelling prospect for therapuetic interventions. In: 10.5772/intechopen.75209 D, editor. Homeostasis - An Integrated Vision. Open access peer-reviewed chapter: IntechOpen Book Series; 2017.
76. Hynes NE, Boulay A. The mTOR pathway in breast cancer. J Mammary Gland Biol Neoplasia. 2006;11(1):53–61. https://doi.org/10.1007/s10911-006-9012-6
77. Fox EM, Miller TW, Balko JM, Kuba MG, Sanchez V, Smith RA, et al. A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res. 2011;71(21):6773–84. https://doi.org/10.1158/0008-5472.CAN-11-1295
78. Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J, et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010;431(2):245–55. https://doi.org/10.1042/BJ20101024
79. Hong SE, Kim EK, Jin HO, Kim HA, Lee JK, Koh JS, et al. S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell Biol Toxicol. 2013;29(4):273–82. https://doi.org/10.1007/s10565-013-9253-2
80. Choi HN, Jin HO, Kim JH, Hong SE, Kim HA, Kim EK, et al. Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2013;432(1):123–8. https://doi.org/10.1016/j.bbrc.2013.01.074
81. Segatto I, Berton S, Sonego M, Massarut S, D’Andrea S, Perin T, et al. Inhibition of breast cancer local relapse by targeting p70S6 kinase activity. J Mol Cell Biol. 2013;5(6):428–31. https://doi.org/10.1093/jmcb/mjt027
82. Segatto I, Massarut S, Boyle R, Baldassarre G, Walker D, Belletti B. Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer. Aging (Albany NY). 2016;8(5):958–76. https://doi.org/10.18632/aging.100954
83. Hollebecque A, Houede N, Cohen EE, Massard C, Italiano A, Westwood P, et al. A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours. Eur J Cancer. 2014;50(5):876–84. https://doi.org/10.1016/j.ejca.2013.12.006
84. Tolcher A, Goldman J, Patnaik A, Papadopoulos KP, Westwood P, Kelly CS, et al. A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours. Eur J Cancer. 2014;50(5):867–75. https://doi.org/10.1016/j.ejca.2013.11.039
85. Chen B, Yang L, Zhang R, Gan Y, Zhang W, Liu D, et al. Hyperphosphorylation of RPS6KB1, rather than overexpression, predicts worse prognosis in non-small cell lung cancer patients. PLoS One. 2017;12(8):e0182891. https://doi.org/10.1371/journal.pone.0182891
86. Bussenius J, Anand NK, Blazey CM, Bowles OJ, Bannen LC, Chan DS, et al. Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors. Bioorg Med Chem Lett. 2012;22(6):2283–6. https://doi.org/10.1016/j.bmcl.2012.01.105
87. Doscas ME, Williamson AJ, Usha L, Bogachkov Y, Rao GS, Xiao F, et al. Inhibition of p70 S6 kinase (S6K1) activity by A77 1726 and its effect on cell proliferation and cell cycle progress. Neoplasia. 2014;16(10):824–34. https://doi.org/10.1016/j.neo.2014.08.006
88. Bandarage U, Hare B, Parsons J, Pham L, Marhefka C, Bemis G, et al. 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors. Bioorg Med Chem Lett. 2009;19(17):5191–4. https://doi.org/10.1016/j.bmcl.2009.07.022
89. Bae EJ, Yang YM, Kim JW, Kim SG. Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway. Hepatology. 2007;46(3):730–9. https://doi.org/10.1002/hep.21769
90. Lee WH, Kim YW, Choi JH, Brooks SC, 3rd, Lee MO, Kim SG. Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect. Mol Cancer Ther. 2009;8(10):2791–802. https://doi.org/10.1158/1535-7163.MCT-09-0420
91. Clapper ML. Chemopreventive activity of oltipraz. Pharmacol Ther. 1998;78(1):17–27. https://doi.org/10.1016/S0163-7258(97)00164-2
92. Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB, et al. Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People’s Republic of China. J Natl Cancer Inst. 1999;91(4):347–54. https://doi.org/10.1093/jnci/91.4.347
93. Ye P, Kuhn C, Juan M, Sharma R, Connolly B, Alton G, et al. Potent and selective thiophene urea-templated inhibitors of S6K. Bioorg Med Chem Lett. 2011;21(2):849–52. https://doi.org/10.1016/j.bmcl.2010.11.069
94. Yin Y, Sun Y, Zhao L, Pan J, Feng Y. Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors. RSC Med Chem. 2020;11(5):583–90. https://doi.org/10.1039/C9MD00537D
95. Sridhar J, Bratton M, Komati R, inventors; Xavier University of Louisiana, assignee. S6K1 protein kinase inhibitors as cancer therapeutics. United States2021.
96. Aletru M, Damour D, Mougenot P, Nardi F, Nemecek P, Philippo C, et al., inventors; Sanofi-Aventis US LLC, assignee. Novel Substituted indazoles, the preparation thereof and use of same in therapeutics. United States2010.
97. Nam KH, Yi SA, Nam G, Noh JS, Park JW, Lee MG, et al. Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer. BMC Cancer. 2019;19(1):773. https://doi.org/10.1186/s12885-019-5997-2
98. Chen J, Sun J, Prinz RA, Li Y, Xu X. Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase. Mol Nutr Food Res. 2018;62(23):e1800709. https://doi.org/10.1002/mnfr.201800709
99. Qin J, Rajaratnam R, Feng L, Salami J, Barber-Rotenberg JS, Domsic J, et al. Development of organometallic S6K1 inhibitors. J Med Chem. 2015;58(1):305-14. https://doi.org/10.1021/jm5011868