S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer (2024)

  • Rolfo C, Giovannetti E, Hong DS, Bivona T, Raez LE, Bronte G, et al. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev. 2014;40:990–1004.

    CAS PubMed Google Scholar

  • Wao H, Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B. Survival of patients with non-small cell lung cancer without treatment: a systematic review and meta-analysis. Syst Rev. 2013;2:10.

    PubMed PubMed Central Google Scholar

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

    CAS PubMed Google Scholar

  • Fujita Y, Suda K, Kimura H, Matsumoto K, Arao T, Nagai T, et al. Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation. J Thorac Oncol. 2012;7:1640–4.

    CAS PubMed Google Scholar

  • Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27:1667–74.

    PubMed PubMed Central Google Scholar

  • Donev IS, Wang W, Yamada T, Li Q, Takeuchi S, Matsumoto K, et al. Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin Cancer Res. 2011;17:2260–9.

    CAS PubMed Google Scholar

  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.

    CAS PubMed Google Scholar

  • Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609–19.

    CAS PubMed PubMed Central Google Scholar

  • Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44:852–60.

    CAS PubMed PubMed Central Google Scholar

  • Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17:5530–7.

    CAS PubMed PubMed Central Google Scholar

  • de Bruin EC, Cowell C, Warne PH, Jiang M, Saunders RE, Melnick MA, et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Disco. 2014;4:606–19.

    Google Scholar

  • Romaniello D, Mazzeo L, Mancini M, Marrocco I, Noronha A, Kreitman M, et al. A combination of approved antibodies overcomes resistance of lung cancer to osimertinib by blocking bypass pathways. Clin Cancer Res. 2018;24:5610–21.

    CAS PubMed Google Scholar

  • Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.

    PubMed PubMed Central Google Scholar

  • Gray JE, Okamoto I, Sriuranpong V, Vansteenkiste J, Imamura F, Lee JS, et al. Tissue and plasma EGFR mutation analysis in the FLAURA trial: osimertinib versus comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer. Clin Cancer Res. 2019;25:6644–52.

    CAS PubMed PubMed Central Google Scholar

  • Fenton TR, Gout IT. Functions and regulation of the 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol. 2011;43:47–59.

    CAS PubMed Google Scholar

  • Bostner J, Karlsson E, Eding CB, Perez-Tenorio G, Franzen H, Konstantinell A, et al. S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts. Endocr Relat Cancer. 2015;22:331–43.

    CAS PubMed Google Scholar

  • Ip CK, Yung S, Chan TM, Tsao SW, Wong AS. p70 S6 kinase drives ovarian cancer metastasis through multicellular spheroid-peritoneum interaction and P-cadherin/b1 integrin signaling activation. Oncotarget. 2014;5:9133–49.

    PubMed Google Scholar

  • Lu Q, Wang J, Yu G, Guo T, Hu C, Ren P. Expression and clinical significance of mammalian target of rapamycin/P70 ribosomal protein S6 kinase signaling pathway in human colorectal carcinoma tissue. Oncol Lett. 2015;10:277–82.

    CAS PubMed PubMed Central Google Scholar

  • Grasso S, Tristante E, Saceda M, Carbonell P, Mayor-Lopez L, Carballo-Santana M, et al. Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. Neoplasia. 2014;16:845–60.

    PubMed PubMed Central Google Scholar

  • Zhang Y, Wang Q, Chen L, Yang HS. Inhibition of p70S6K1 activation by Pdcd4 overcomes the resistance to an IGF-1R/IR inhibitor in colon carcinoma cells. Mol Cancer Ther. 2015;14:799–809.

    CAS PubMed PubMed Central Google Scholar

  • Ju L, Zhou C, Li W, Yan L. Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. J Cell Biochem. 2010;111:1565–74.

    CAS PubMed Google Scholar

  • Koizumi F, Shimoyama T, Taguchi F, Saijo N, Nishio K. Establishment of a human non-small cell lung cancer cell line resistant to gefitinib. Int J Cancer. 2005;116:36–44.

    CAS PubMed Google Scholar

  • Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, Barbu V, Fartoux L, Poupon R, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer. 2006;119:2557–66.

    CAS PubMed Google Scholar

  • Jacobsen K, Bertran-Alamillo J, Molina MA, Teixido C, Karachaliou N, Pedersen MH, et al. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nat Commun. 2017;8:410.

    PubMed PubMed Central Google Scholar

  • Jiang X, Sinnett-Smith J, Rozengurt E. Carbachol induces p70S6K1 activation through an ERK-dependent but Akt-independent pathway in human colonic epithelial cells. Biochem Biophys Res Commun. 2009;387:521–4.

    CAS PubMed PubMed Central Google Scholar

  • Qi HW, Shen Z, Fan LH. Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line. Exp Ther Med. 2011;2:1091–5.

    CAS PubMed PubMed Central Google Scholar

  • McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5:a008656.

    PubMed PubMed Central Google Scholar

  • Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, et al. Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem. 1999;274:22932–40.

    CAS PubMed Google Scholar

  • Qiu ZX, Sun RF, Mo XM, Li WM. The p70S6K specific inhibitor PF-4708671 impedes non-small cell lung cancer growth. PLoS ONE. 2016;11:e0147185.

    PubMed PubMed Central Google Scholar

  • Fang J, Meng Q, Vogt PK, Zhang R, Jiang BH. A downstream kinase of the mammalian target of rapamycin, p70S6K1, regulates human double minute 2 protein phosphorylation and stability. J Cell Physiol. 2006;209:261–5.

    CAS PubMed Google Scholar

  • Valovka T, Verdier F, Cramer R, Zhyvoloup A, Fenton T, Rebholz H, et al. Protein kinase C phosphorylates ribosomal protein S6 kinase betaII and regulates its subcellular localization. Mol Cell Biol. 2003;23:852–63.

    CAS PubMed PubMed Central Google Scholar

  • Lai KP, Leong WF, Chau JF, Jia D, Zeng L, Liu H, et al. S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J. 2010;29:2994–3006.

    CAS PubMed PubMed Central Google Scholar

  • Park HS, Park JM, Park S, Cho J, Kim SI, Park BW. Subcellular localization of Mdm2 expression and prognosis of breast cancer. Int J Clin Oncol. 2014;19:842–51.

    CAS PubMed Google Scholar

  • Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9.

    CAS PubMed Google Scholar

  • Wang W, Qin JJ, Voruganti S, Srivenugopal KS, Nag S, Patil S, et al. The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun. 2014;5:5086.

    CAS PubMed PubMed Central Google Scholar

  • Juchum M, Gunther M, Laufer SA. Fighting cancer drug resistance: opportunities and challenges for mutation-specific EGFR inhibitors. Drug Resist Updat. 2015;20:12–28.

    PubMed Google Scholar

  • Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat. 2008;11:63–76.

    CAS PubMed PubMed Central Google Scholar

  • Yu HA, Suzawa K, Jordan E, Zehir A, Ni A, Kim R, et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin Cancer Res. 2018;24:3108–18.

    CAS PubMed PubMed Central Google Scholar

  • Shin S, Wolgamott L, Yu Y, Blenis J, Yoon SO. Glycogen synthase kinase (GSK)-3 promotes p70 ribosomal protein S6 kinase (p70S6K) activity and cell proliferation. Proc Natl Acad Sci USA. 2011;108:E1204–13.

    PubMed Google Scholar

  • Bilanges B, Vanhaesebroeck B. A new tool to dissect the function of p70 S6 kinase. Biochem J. 2010;431:e1–e3.

    CAS PubMed Google Scholar

  • Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26:1932–40.

    CAS PubMed Google Scholar

  • 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;431:245–55.

    CAS PubMed Google Scholar

  • 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;6:361–76.

    PubMed PubMed Central Google Scholar

  • 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;50:876–84.

    CAS PubMed Google Scholar

  • 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;50:867–75.

    CAS PubMed Google Scholar

  • 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.

    CAS PubMed Google Scholar

  • Eischen CM. Role of Mdm2 and Mdmx in DNA repair. J Mol Cell Biol. 2017;9:69–73.

    CAS PubMed PubMed Central Google Scholar

  • Feeley KP, Adams CM, Mitra R, Eischen CM. Mdm2 is required for survival and growth of p53-deficient cancer cells. Cancer Res. 2017;77:3823–33.

    CAS PubMed PubMed Central Google Scholar

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    CAS PubMed Google Scholar

  • Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci USA. 2008;105:3933–8.

    CAS PubMed Google Scholar

  • Wykosky J, Hu J, Gomez GG, Taylor T, Villa GR, Pizzo D, et al. A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma. Cancer Res. 2015;75:394–404.

    CAS PubMed Google Scholar

  • Phuchareon J, McCormick F, Eisele DW, Tetsu O. EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function. Proc Natl Acad Sci USA. 2015;112:E3855–63.

    CAS PubMed Google Scholar

  • Ashton JC. Drug combination studies and their synergy quantification using the Chou-Talalay method-letter. Cancer Res. 2015;75:2400.

    CAS PubMed Google Scholar

  • Wang Y, Deng X, Yu C, Zhao G, Zhou J, Zhang G, et al. Synergistic inhibitory effects of capsaicin combined with cisplatin on human osteosarcoma in culture and in xenografts. J Exp Clin Cancer Res. 2018;37:251.

    CAS PubMed PubMed Central Google Scholar

  • Zhang C, Hao L, Wang L, Xiao Y, Ge H, Zhu Z, et al. Elevated IGFIR expression regulating VEGF and VEGF-C predicts lymph node metastasis in human colorectal cancer. BMC Cancer. 2010;10:184.

    PubMed PubMed Central Google Scholar

  • S6K1 blockade overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer (2024)
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