Evolution from genetics to phenotype: reinterpretation of NSCLC plasticity, heterogeneity, and drug resistance

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy is beneficial in most cases, but the development of drug resistance stands as an obstacle to good prognosis. Multiple mechanisms were explored such as genetic alterations, activation of bypass signaling, and phenotypic transition. These intrinsic and/or extrinsic dynamic regulations facilitate tumor cell survival in meeting the demands of signaling under different stimulus. This review introduces lung cancer plasticity and heterogeneity and their correlation with drug resistance. While cancer plasticity and heterogeneity play an essential role in the development of drug resistance, the manipulation of them may bring some inspirations to cancer prognosis and treatment. That is to say, lung cancer plasticity and heterogeneity present us with not only challenges but also opportunities.

Keywords

lung cancer / plasticity / heterogeneity / drug resistance / phenotypic transition

References

[1] Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104:20932–20937

[2] Bischof AG, Yuksel D, Mammoto T, Mammoto A, Krause S, Ingber DE (2013) Breast cancer normalization induced by embryonic mesenchyme is mediated by extracellular matrix biglycan. Integr Biol (Camb) 5:1045–1056

[3] Brock A, Krause S, Ingber DE (2015) Control of cancer formation by intrinsic genetic noise and microenvironmental cues. Nat Rev Cancer 15:499–509

[4] Calikusu Z, Yildirim Y, Akcali Z, Sakalli H, Bal N, Unal I, Ozyilkan O (2009) The effect of HER2 expression on cisplatin-based chemotherapy in advanced non-small cell lung cancer patients. J Exp Clin Cancer Res 28:97

[5] Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 108:7950–7955

[6] Cheng J, Qi J, Li XT, Zhou K, Xu JH, Zhou Y, Zhang GQ, Xu JP, Zhou RJ (2015) ATRA and Genistein synergistically inhibit the metastatic potential of human lung adenocarcinoma cells. Int J Clin Exp Med 8:4220–4227

[7] Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739

[8] Ciardiello F (2000) Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer agents. Drugs 60(Suppl 1) 25–32; discussion 41–22

[9] Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P (2014) Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346:1480–1486

[10] Denis MG, Vallee A, Theoleyre S (2015) EGFR T790M resistance mutation in non small-cell lung carcinoma. Clin Chim Acta 444:81–85

[11] Dibben SM, Holt RJ, Davison TS, Wilson CL, Taylor J, Paul I, McManus K, Kelly PJ, Proutski V, Harkin DP (2012) Implications for powering biomarker discovery studies. J Mol Diagn 14:130–139

[12] Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482

[13] Engelman JA, Janne PA (2008) Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 14:2895–2899

[14] Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

[15] Frederick BA, Helfrich BA, Coldren CD, Zheng D, Chan D, Bunn PA Jr, Raben D (2007) Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 6:1683–1691

[16] Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29:2866–2874

[17] Gao Y, Zhang W, Han X, Li F, Wang X, Wang R, Fang Z, Tong X, Yao S, Li F (2014) YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression. Nat Commun 5:4629

[18] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892

[19] Greve G, Schiffmann I, Lubbert M (2015) Epigenetic priming of nonsmall cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid. J Cancer Res Clin Oncol 141:2171–2180

[20] Guan DX, Shi J, Zhang Y, Zhao JS, Long LY, Chen TW, Zhang EB, Feng YY, Bao WD, Deng YZ (2015) Sorafenib enriches epithelial cell adhesion molecule-positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2-AKT cascade. Hepatology 62:1791–1803

[21] Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138:645–659

[22] Gurden MD, Westwood IM, Faisal A, Naud S, Cheung KM, McAndrew C, Wood A, Schmitt J, Boxall K, Mak G (2015) Naturally occurring mutations in the MPS1 gene predispose cells to kinase inhibitor drug resistance. Cancer Res 75:3340–3354

[23] Han X, Li F, Fang Z, Gao Y, Li F, Fang R, Yao S, Sun Y, Li L, Zhang W (2014) Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma. Nat Commun 5:3261

[24] Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H (2015) Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib. Cancer Sci 106:1377–1384

[25] Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, Maruvka YE, Ji F, Bhang HC, Krishnamurthy Radhakrishna V (2016) Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 5:24

[26] Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807

[27] Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276

[28] Hofmann HS, Knolle J, Neef H (1994) The adenosquamous lung carcinoma: clinical and pathological characteristics. J Cardiovasc Surg (Torino) 35:543–547

[29] Hsieh MS, Jhuang JY, Hua SF, Chou YH (2015) Histologic evolution from adenocarcinoma to squamous cell carcinoma after gefitinib treatment. Ann Thorac Surg 99:316–319

[30] Iams WT, Lovly CM (2015) Anaplastic lymphoma kinase as a therapeutic target in non-small cell lung cancer. Cancer J 21:378–382

[31] Ichinokawa H, Ishii G, Nagai K, Yoshida J, Nishimura M, Hishida T, Suzuki K, Ochiai A (2011) Clinicopathological characteristics of primary lung adenocarcinoma predominantly composed of goblet cells in surgically resected cases. Pathol Int 61:423–429

[32] Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R, Jacks T, Tuveson DA (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15:3243–3248

[33] Jeong SH, Jung JH, Han JH, Kim JH, Choi YW, Lee HW, Kang SY, Hwang YH, Ahn MS, Choi JH (2010) Expression of Bcl-2 predicts outcome in locally advanced non-small cell lung cancer patients treated with cisplatin-based concurrent chemoradiotherapy. Lung Cancer 68:288–294

[34] Kang SM, Kang HJ, Shin JH, Kim H, Shin DH, Kim SK, Kim JH, Chung KY, Kim SK, Chang J (2007) Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer 109:581–587

[35] Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 4:120ra17

[36] Katayama R, Friboulet L, Koike S, Lockerman EL, Khan TM, Gainor JF, Iafrate AJ, Takeuchi K, Taiji M, Okuno Y (2014) Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 20:5686–5696

[37] Key J, Kim YS, Tatulli F, Palange AL, O’Neill B, Aryal S, Ramirez M, Liu X, Ferrari M, Munden R (2014) Opportunities for nanotheranosis in lung cancer and pulmonary metastasis. Clin Transl Imaging 2:427–437

[38] Kim ES, Tang X, Peterson DR, Kilari D, Chow CW, Fujimoto J, Kalhor N, Swisher SG, Stewart DJ, Wistuba II (2014) Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. Lung Cancer 85:88–93

[39] Kim HJ, Lee KY, Kim YW, Choi YJ, Lee JE, Choi CM, Baek IJ, Rho JK, Lee JC (2015) P-glycoprotein confers acquired resistance to 17-DMAG in lung cancers with an ALK rearrangement. BMC Cancer 15:553

[40] Kong FF, Zhu YL, Yuan HH, Wang JY, Zhao M, Gong XD, Liu F, Zhang WY, Wang CR, Jiang B (2014) FOXM1 regulated by ERK pathway mediates TGF-beta1-induced EMT in NSCLC. Oncol Res 22:29–37

[41] Krause S, Maffini MV, Soto AM, Sonnenschein C(2010) The microenvironment determines the breast cancer cells’ phenotype: organization of MCF7 cells in 3D cultures. BMC Cancer 10:263

[42] Kuiper JL, Ronden MI, Becker A, Heideman DA, van Hengel P, Ylstra B, Thunnissen E, Smit EF (2015) Transformation to a squamous cell carcinoma phenotype of an EGFR-mutated NSCLC patient after treatment with an EGFR-tyrosine kinase inhibitor. J Clin Pathol 68:320–321

[43] Lee LM, Seftor EA, Bonde G, Cornell RA, Hendrix MJ (2005) The fate of human malignant melanoma cells transplanted into zebrafish embryos: assessment of migration and cell division in the absence of tumor formation. Dev Dyn 233:1560–1570

[44] Li B, Gao MH, Lv CY, Yang P, Yin QF (2015a) Study of the synergistic effects of all-transretinoic acid and C-phycocyanin on the growth and apoptosis of A549 cells. Eur J Cancer Prev 25:97–101

[45] Li F, Han X, Li F, Wang R, Wang H, Gao Y, Wang X, Fang Z, Zhang W, Yao S (2015b) LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell 27:698–711

[46] Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, Florin A, Ozretic L, Lim D, Wang L (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027–1034

[47] Marjanovic ND, Weinberg RA, Chaffer CL (2013) Cell plasticity and heterogeneity in cancer. Clin Chem 59:168–179

[48] Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805:105–117

[49] Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341:1165–1173

[50] Merrill RA, Ahrens JM, Kaiser ME, Federhart KS, Poon VY, Clagett-Dame M (2004) All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblastoma cell line and their regulated expression in the nervous system of early embryos. Biol Chem 385:605–614

[51] Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, Krug LM, Pao W, Rizvi N, Pizzo B (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103–1109

[52] Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589

[53] Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K, Satou T, Nishio K, Fukuoka M, Nakagawa K (2007) Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer 58:411–413

[54] Moro M, Bertolini G, Pastorino U, Roz L, Sozzi G (2015) Combination treatment with all-trans retinoic acid prevents cisplatininduced enrichment of CD133+ tumor-initiating cells and reveals heterogeneity of cancer stem cell compartment in lung cancer. J Thorac Oncol 10:1027–1036

[55] Nakanishi Y, Kawasaki M, Bai F, Takayama K, Pei XH, Takano K, Inoue K, Osaki S, Hara N, Kiyohara C (1999) Expression of p53 and glutathione S-transferase-pi relates to clinical drug resistance in non-small cell lung cancer. Oncology 57:318–323

[56] Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T (2015) RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 6:6377

[57] Norkowski E, Ghigna MR, Lacroix L, Le Chevalier TFadel E, Dartevelle P, Dorfmuller P, Thomas de Montpreville V, (2013) Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol 8:1265–1271

[58] Nurwidya F, Takahashi F, Murakami A, Takahashi K (2012) Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res Treat 44:151–156

[59] Oh JE, An CH, Yoo NJ, Lee SH (2011) Detection of low-level EGFR T790M mutation in lung cancer tissues. APMIS 119:403–411

[60] Olaussen KA, Postel-Vinay S (2016) Predictors of chemotherapy efficacy in Non-Small Cell Lung Cancer: a challenging landscape. Ann Oncol mdw321

[61] Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

[62] Park DH, Jeon HS, Lee SY, Choi YY, Lee HW, Yoon S, Lee JC, Yoon YS, Kim DS, Na MJ (2015) MicroRNA-146a inhibits epithelial mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2. Int J Oncol 75:186

[63] Perez-Ramirez C, Canadas-Garre M, Jimenez-Varo E, Faus-Dader MJ, Calleja-Hernandez MA (2015) MET: a new promising biomarker in non-small-cell lung carcinoma. Pharmacogenomics 16:631–647

[64] Ren J, Chen Y, Song H, Chen L, Wang R (2013) Inhibition of ZEB1 reverses EMT and chemoresistance in docetaxel-resistant human lung adenocarcinoma cell line. J Cell Biochem 114:1395–1403

[65] Riely GJ, Yu HA (2015) EGFR: the paradigm of an oncogene-driven lung cancer. Clin Cancer Res 21:2221–2226

[66] Santarpia M, Gil N, Rosell R (2015) Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Expert Rev Clin Pharmacol 8:461–477

[67] Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K (2011) A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:6051–6060

[68] Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75

[69] Shaw AT, Hsu PP, Awad MM, Engelman JA (2013) Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer 13:772–787

[70] Shea M, Costa DB, Rangachari D (2016) Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis 10:113–129

[71] Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, Hashida S, Maki Y, Ichihara E, Asano H (2013) Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res 73:3051–3061

[72] Shien K, Yamamoto H, Soh J, Miyoshi S, Toyooka S (2014) Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. Acta Med Okayama 68:191–200

[73] Shoshani O, Zipori D (2015) Stress as a fundamental theme in cell plasticity. Biochim Et Biophys Acta-Gene Regul Mech 1849:371–377

[74] Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H (2007) Identification of the transforming EML4-ALK fusion gene in nonsmall-cell lung cancer. Nature 448:561–566

[75] Suda K, Tomizawa K, Fujii M, Murakami H, Osada H, Maehara Y, Yatabe Y, Sekido Y, Mitsudomi T (2011) Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J Thorac Oncol 6:1152–1161

[76] Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A (2015) Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitors in non-small cell lung cancer. Mol Cancer Ther 14:2433–2440

[77] Sui H, Zhu L, Deng W, Li Q (2014) Epithelial-mesenchymal transition and drug resistance: role, molecular mechanisms, and therapeutic strategies. Oncol Res Treat 37:584–589

[78] Sun Y, Daemen A, Hatzivassiliou G, Arnott D, Wilson C, Zhuang G, Gao M, Liu P, Boudreau A, Johnson L (2014) Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells. Cancer Metab 2:20

[79] Sutherland KD, Berns A (2010) Cell of origin of lung cancer. Mol Oncol 4:397–403

[80] Takezawa K, Pirazzoli V,Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA (2012) HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2:922–933

[81] Tanimoto A, Yamada T, Nanjo S, Takeuchi S, Ebi H, Kita K, Matsumoto K, Yano S (2014) Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. Oncotarget 5:4920–4928

[82] Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelialmesenchymal transitions in development and disease. Cell 139:871–890

[83] Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y (2015) Acquired EGFR C797S mutation mediates resistance to AZD9291 in nonsmall cell lung cancer harboring EGFR T790M. Nat Med 21:560–562

[84] Toyooka S, Yatabe Y, Tokumo M, Ichimura K, Asano H, Tomii K, Aoe M, Yanai H, Date H, Mitsudomi T (2006) Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung. Int J Cancer 118:1588–1590

[85] Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88

[86] Turtoi A, Blomme A, Castronovo V (2015) Intratumoral heterogeneity and consequences for targeted therapies. Bull Cancer 102:17–23

[87] Tuveson DA, Jacks T (1999) Modeling human lung cancer in mice: similarities and shortcomings. Oncogene 18:5318–5324

[88] Uramoto H, Iwata T, Onitsuka T, Shimokawa H, Hanagiri T, Oyama T (2010) Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res 30:2513–2517

[89] Wang H, Guo R, Zhang L (2015) TKI Resistance for T790M Mutation. Zhongguo Fei Ai Za Zhi 18:245–250

[90] Watanabe M, Kawaguchi T, Isa S, Ando M, Tamiya A, Kubo A, Saka H, Takeo S, Adachi H, Tagawa T (2015) Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res 21:3552–3560

[91] Weinberg R (2013) The biology of cancer. Garland science

[92] Wilson C, Nicholes K, Bustos D, Lin E, Song Q, Stephan JP, Kirkpatrick DS, Settleman J (2014) Overcoming EMT-associated resistance to anti-cancer drugs via Src/FAK pathway inhibition. Oncotarget 5:7328–7341

[93] Wilson FH, Johannessen CM, Piccioni F, Tamayo P, Kim JW, Van Allen EM, Corsello SM, Capelletti M, Calles A, Butaney M (2015) A functional landscape of resistance to ALK inhibition in lung cancer. Cancer Cell 27:397–408

[94] Xin H, Kong Y, Jiang X, Wang K, Qin X, Miao ZH, Zhu Y, Tan W (2013) Multi-drug-resistant cells enriched from chronic myeloid leukemia cells by Doxorubicin possess tumor-initiating-cell properties. J Pharmacol Sci 122:299–304

[95] Yamaguchi N, Lucena-Araujo AR, Nakayama S, de Figueiredo-Pontes LL, Gonzalez DA, Yasuda H, Kobayashi S, Costa DB (2014) Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. Lung Cancer 83:37–43

[96] Yang J, Qin G, Luo M, Chen J, Zhang Q, Li L, Pan L, Qin S (2015) Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT. Cell Death Dis 6:e1829

[97] Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, Ladanyi M (2015) Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 1:982–984

[98] Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 105:2070–2075

[99] Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–39

[100] Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Su L, Christiani DC (2004) Excision repair crosscomplementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 10:4939–4943

[101] Zhou RJ, Yang XQ, Wang D, Zhou Q, Xia L, Li MX, Zeng LL, Wang G, Yang ZZ (2012) Anti-tumor effects of all-trans retinoic acid are enhanced by genistein. Cell Biochem Biophys 62:177–184

RIGHTS & PERMISSIONS

The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn