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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992


Computational Analysis of Drug Resistance Network in Lung Adenocarcinoma

Author(s): Altan Kara*, Aykut Özgür, Şaban Tekin and Yusuf Tutar

Volume 22, Issue 3, 2022

Published on: 18 February, 2021

Page: [566 - 578] Pages: 13

DOI: 10.2174/1871520621666210218175439

Price: $65


Background: Lung cancer is a significant health problem and accounts for one-third of the deaths worldwide. A great majority of these deaths are caused by Non-Small Cell Lung Cancer (NSCLC). Chemotherapy is the leading treatment method for NSCLC, but resistance to chemotherapeutics is an important limiting factor that reduces the treatment success of patients with NSCLC.

Objective: In this study, the relationship between differentially expressed genes affecting the survival of the patients, according to the bioinformatics analyses, and the mechanism of drug resistance is investigated for nonsmall cell lung adenocarcinoma patients.

Methods: Five hundred thirteen patient samples were compared with fifty-nine control samples. The employed dataset was downloaded from The Cancer Genome Atlas (TCGA) database. The information on how the drug activity altered against the expressional diversification of the genes was extracted from the NCI-60 database. Four hundred thirty-three drugs with known Mechanism of Action (MoA) were analyzed. Diversifications of the activity of these drugs related to genes were considered based on nine lung cancer cell lines virtually. The analyses were performed using R programming language, GDCRNATools, rcellminer, and Cytoscape.

Results: This work analyzed the common signaling pathways and expressional alterations of the proteins in these pathways associated with survival and drug resistance in lung adenocarcinoma. Deduced computational data demonstrated that proteins of EGFR, JNK/MAPK, NF-κB, PI3K /AKT/mTOR, JAK/STAT, and Wnt signaling pathways were associated with the molecular mechanism of resistance to anticancer drugs in NSCLC cells.

Conclusion: To understand the relationships between resistance to anticancer drugs and EGFR, JNK/MAPK, NF-κB, PI3K /AKT/mTOR, JAK/STAT, and Wnt signaling pathways is an important approach to design effective therapeutics for individuals with NSCLC adenocarcinoma.

Keywords: Lung cancer, non-small cell lung cancer, drug resistance, adenocarcinoma, transcriptome, computational analysis.

Graphical Abstract
Dela Cruz, C.S.; Tanoue, L.T.; Matthay, R.A. Lung cancer: epidemiology, etiology, and prevention. Clin. Chest Med., 2011, 32(4), 605-644.
[] [PMID: 22054876]
de Groot, P.; Munden, R.F. Lung cancer epidemiology, risk factors, and prevention. Radiol. Clin. North Am., 2012, 50(5), 863-876.
[] [PMID: 22974775]
Tutar, Y.; Özgür, A.; Tutar, E.; Tutar, L.; Pulliero, A.; Izzotti, A. Regulation of oncogenic genes by MicroRNAs and pseudogenes in human lung cancer. Biomed. Pharmacother., 2016, 83, 1182-1190.
[] [PMID: 27551766]
Walker, S. Updates in non-small cell lung cancer. Clin. J. Oncol. Nurs., 2008, 12(4), 587-596.
[] [PMID: 18676326]
Bade, B.C.; Dela Cruz, C.S. Lung Cancer 2020: epidemiology, etiology, and prevention. Clin. Chest Med., 2020, 41(1), 1-24.
[] [PMID: 32008623]
Zhang, Y.; Wang, H.; Wang, J.; Bao, L.; Wang, L.; Huo, J.; Wang, X. Global analysis of chromosome 1 genes among patients with lung adenocarcinoma, squamous carcinoma, large-cell carcinoma, small-cell carcinoma, or non-cancer. Cancer Metastasis Rev., 2015, 34(2), 249-264.
[] [PMID: 25937073]
Ali, A.; Goffin, J.R.; Arnold, A.; Ellis, P.M. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr. Oncol., 2013, 20(4), e300-e306.
[] [PMID: 23904768]
Zappa, C.; Mousa, S.A. Non-small cell lung cancer: current treatment and future advances. Transl. Lung Cancer Res., 2016, 5(3), 288-300.
[] [PMID: 27413711]
Shiran, I.; Heller, E.; Jessel, S.; Kamer, I.; Daniel-Meshulam, I.; Navon, R.; Urban, D.; Onn, A.; Bar, J. Non-small-cell lung cancer patients with adenocarcinoma morphology have a better outcome compared with patients diagnosed with non-small-cell lung cancer favor adenocarcinoma. Clin. Lung Cancer, 2017, 18(3), 316-323.
[] [PMID: 28237243]
Maas, K.W.; El Sharouni, S.Y.; Smit, E.F.; Schramel, F.M.N.H. Sequencing chemotherapy, radiotherapy and surgery in combined modality treatment of stage III nonsmall cell lung cancer. Curr. Opin. Pulm. Med., 2007, 13(4), 297-304.
[] [PMID: 17534176]
Farhat, F.S.; Houhou, W. Targeted therapies in non-small cell lung carcinoma: what have we achieved so far? Ther. Adv. Med. Oncol., 2013, 5(4), 249-270.
[] [PMID: 23858333]
Tsvetkova, E.; Goss, G.D. Drug resistance and its significance for treatment decisions in non-small-cell lung cancer. Curr. Oncol., 2012, 19(1)(Suppl. 1), S45-S51.
[PMID: 22787410]
Wangari-Talbot, J.; Hopper-Borge, E. Drug resistance mechanisms in non-small cell lung carcinoma. J. Cancer Res. Updates, 2013, 2(4), 265-282.
[PMID: 24634705]
da Cunha Santos, G.; Shepherd, F.A.; Tsao, M.S. EGFR mutations and lung cancer. Annu. Rev. Pathol., 2011, 6, 49-69.
[] [PMID: 20887192]
Lin, J.J.; Shaw, A.T. Resisting resistance: targeted therapies in lung cancer. Trends Cancer, 2016, 2(7), 350-364.
[] [PMID: 27819059]
Li, J.; Kwok, H.F. Current strategies for treating NSCLC: from biological mechanisms to clinical treatment. Cancers (Basel), 2020, 12(6), 1587.
[] [PMID: 32549388]
Gao, J.; Li, H.R.; Jin, C.; Jiang, J.H.; Ding, J.Y. Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer. Clin. Transl. Oncol., 2019, 21(10), 1287-1301.
[] [PMID: 30864018]
Rasmi, R.R.; Sakthivel, K.M.; Guruvayoorappan, C. NF-κB inhibitors in treatment and prevention of lung cancer. Biomed. Pharmacother., 2020, 130110569
[] [PMID: 32750649]
Liu, L.; Zhu, H.; Liao, Y.; Wu, W.; Liu, L.; Liu, L.; Wu, Y.; Sun, F.; Lin, H.W. Inhibition of Wnt/β-catenin pathway reverses multi-drug resistance and EMT in Oct4+/Nanog+ NSCLC cells. Biomed. Pharmacother., 2020, 127110225
[] [PMID: 32428834]
Liu, W.J.; Du, Y.; Wen, R.; Yang, M.; Xu, J. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol. Ther., 2020, 206107438
[] [PMID: 31715289]
Lin, Y.; Wang, X.; Jin, H. EGFR-TKI resistance in NSCLC patients: mechanisms and strategies. Am. J. Cancer Res., 2014, 4(5), 411-435.
[PMID: 25232485]
Tomczak, K.; Czerwińska, P.; Wiznerowicz, M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp. Oncol. (Pozn.), 2015, 19(1A), A68-A77.
[] [PMID: 25691825]
Li, R.; Qu, H.; Wang, S.; Wei, J.; Zhang, L.; Ma, R.; Lu, J.; Zhu, J.; Zhong, W.D.; Jia, Z. GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. Bioinformatics, 2018, 34(14), 2515-2517.
[] [PMID: 29509844]
Law, C.W.; Chen, Y.; Shi, W.; Smyth, G.K. voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol., 2014, 15(2), R29.
[] [PMID: 24485249]
Ritchie, M.E.; Phipson, B.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 2015, 43(7)e47
[] [PMID: 25605792]
Lacny, S.; Wilson, T.; Clement, F.; Roberts, D.J.; Faris, P.; Ghali, W.A.; Marshall, D.A. Kaplan-Meier survival analysis overestimates cumulative incidence of health-related events in competing risk settings: a meta-analysis. J. Clin. Epidemiol., 2018, 93, 25-35.
[] [PMID: 29045808]
Liu, H.; D’Andrade, P.; Fulmer-Smentek, S.; Lorenzi, P.; Kohn, K.W.; Weinstein, J.N.; Pommier, Y.; Reinhold, W.C. mRNA and microRNA expression profiles of the NCI-60 integrated with drug activities. Mol. Cancer Ther., 2010, 9(5), 1080-1091.
[] [PMID: 20442302]
Luna, A.; Rajapakse, V.N.; Sousa, F.G.; Gao, J.; Schultz, N.; Varma, S.; Reinhold, W.; Sander, C.; Pommier, Y. rcellminer: exploring molecular profiles and drug response of the NCI-60 cell lines in R. Bioinformatics, 2016, 32(8), 1272-1274.
[] [PMID: 26635141]
Crosara, K.T.B.; Moffa, E.B.; Xiao, Y.; Siqueira, W.L. Merging in silico and in vitro salivary protein complex partners using the STRING database: a tutorial. J. Proteomics, 2018, 171, 87-94.
[] [PMID: 28782718]
Doncheva, N.T.; Morris, J.H.; Gorodkin, J.; Jensen, L.J. Cytoscape StringApp: network analysis and visualization of proteomics data. J. Proteome Res., 2019, 18(2), 623-632.
[] [PMID: 30450911]
Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal Growth Factor Receptor (EGFR) signaling in cancer. Gene, 2006, 366(1), 2-16.
[] [PMID: 16377102]
Nicholson, R.I.; Gee, J.M.; Harper, M.E. EGFR and cancer prognosis. Eur. J. Cancer, 2001, 37(4)(Suppl. 4), S9-S15.
[] [PMID: 11597399]
Herbst, R.S. Review of epidermal growth factor receptor biology. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(2)(Suppl.), 21-26.
[] [PMID: 15142631]
Sasada, T.; Azuma, K.; Ohtake, J.; Fujimoto, Y. Immune responses to Epidermal Growth Factor Receptor (EGFR) and their application for cancer treatment. Front. Pharmacol., 2016, 7, 405.
[] [PMID: 27833557]
Wieduwilt, M.J.; Moasser, M.M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci., 2008, 65(10), 1566-1584.
[] [PMID: 18259690]
Ciardiello, F.; De Vita, F.; Orditura, M.; Tortora, G. The role of EGFR inhibitors in nonsmall cell lung cancer. Curr. Opin. Oncol., 2004, 16(2), 130-135.
[] [PMID: 15075904]
Tiseo, M.; Loprevite, M.; Ardizzoni, A. Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. Curr. Med. Chem. Anticancer Agents, 2004, 4(2), 139-148.
[] [PMID: 15032719]
Khalil, M.Y.; Grandis, J.R.; Shin, D.M. Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer. Expert Rev. Anticancer Ther., 2003, 3(3), 367-380.
[] [PMID: 12820779]
Johnston, J.B.; Navaratnam, S.; Pitz, M.W.; Maniate, J.M.; Wiechec, E.; Baust, H.; Gingerich, J.; Skliris, G.P.; Murphy, L.C.; Los, M. Targeting the EGFR pathway for cancer therapy. Curr. Med. Chem., 2006, 13(29), 3483-3492.
[] [PMID: 17168718]
Seshacharyulu, P.; Ponnusamy, M.P.; Haridas, D.; Jain, M.; Ganti, A.K.; Batra, S.K. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets, 2012, 16(1), 15-31.
[] [PMID: 22239438]
Harari, P.M. Epidermal growth factor receptor inhibition strategies in oncology. Endocr. Relat. Cancer, 2004, 11(4), 689-708.
[] [PMID: 15613446]
Modjtahedi, H.; Essapen, S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs, 2009, 20(10), 851-855.
[] [PMID: 19826350]
Maione, P.; Rossi, A.; Bareschino, M.; Sacco, P.C.; Schettino, C.; Casaluce, F.; Sgambato, A.; Gridelli, C. Irreversible EGFR inhibitors in the treatment of advanced NSCLC. Curr. Pharm. Des., 2014, 20(24), 3894-3900.
[] [PMID: 24138713]
Stewart, E.L.; Tan, S.Z.; Liu, G.; Tsao, M.S. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl. Lung Cancer Res., 2015, 4(1), 67-81.
[PMID: 25806347]
Ahsan, A. Mechanisms of resistance to EGFR tyrosine kinase inhibitors and therapeutic approaches: an update. Adv. Exp. Med. Biol., 2016, 893, 137-153.
[] [PMID: 26667342]
Charpidou, A.; Blatza, D.; Anagnostou, V.; Syrigos, K.N.; Syrigos, K.N. Review. EGFR mutations in non-small cell lung cancer-clinical implications. In Vivo, 2008, 22(4), 529-536.
[PMID: 18712184]
Chan, B.A.; Hughes, B.G.M. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl. Lung Cancer Res., 2015, 4(1), 36-54.
[PMID: 25806345]
Tumbrink, H.L.; Heimsoeth, A.; Sos, M.L. The next tier of EGFR resistance mutations in lung cancer. Oncogene, 2021, 40(1), 1-11.
[] [PMID: 33060857]
Wang, J.; Wang, B.; Chu, H.; Yao, Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. OncoTargets Ther., 2016, 9, 3711-3726.
[] [PMID: 27382309]
Li, A.R.; Chitale, D.; Riely, G.J.; Pao, W.; Miller, V.A.; Zakowski, M.F.; Rusch, V.; Kris, M.G.; Ladanyi, M. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J. Mol. Diagn., 2008, 10(3), 242-248.
[] [PMID: 18403609]
Siegelin, M.D.; Borczuk, A.C. Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab. Invest., 2014, 94(2), 129-137.
[] [PMID: 24378644]
Gazdar, A.F. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 2009, 28(1)(Suppl. 1), S24-S31.
[] [PMID: 19680293]
Ayoola, A.; Barochia, A.; Belani, K.; Belani, C.P. Primary and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: an update. Cancer Invest., 2012, 30(5), 433-446.
[] [PMID: 22571344]
Wang, S.; Cang, S.; Liu, D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J. Hematol. Oncol., 2016, 9, 34.
[] [PMID: 27071706]
Janku, F.; Stewart, D.J.; Kurzrock, R. Targeted therapy in non-small-cell lung cancer-is it becoming a reality? Nat. Rev. Clin. Oncol., 2010, 7(7), 401-414.
[] [PMID: 20551945]
Jiang, B.H.; Liu, L.Z. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv. Cancer Res., 2009, 102, 19-65.
[] [PMID: 19595306]
Zhao, X.; Xu, M.; Cai, Z.; Yuan, W.; Cui, W.; Li, M.D. Identification of LIFR, PIK3R1, and MMP12 as novel prognostic signatures in gallbladder cancer using network-based module analysis. Front. Oncol., 2019, 9, 325.
[] [PMID: 31119098]
Zhang, H.Y.; Gu, Y.Y.; Li, Z.G.; Jia, Y.H.; Yuan, L.; Li, S.Y.; An, G.S.; Ni, J.H.; Jia, H.T. Exposure of human lung cancer cells to 8-chloro-adenosine induces G2/M arrest and mitotic catastrophe. Neoplasia, 2004, 6(6), 802-812.
[] [PMID: 15720807]
Solinas, G.; Becattini, B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol. Metab., 2016, 6(2), 174-184.
[] [PMID: 28180059]
Kim, E.K.; Choi, E.J. Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta, 2010, 1802(4), 396-405.
[] [PMID: 20079433]
Wagner, E.F.; Nebreda, A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer, 2009, 9(8), 537-549.
[] [PMID: 19629069]
Tournier, C. The 2 Faces of JNK Signaling in Cancer. Genes Cancer, 2013, 4(9-10), 397-400.
[] [PMID: 24349637]
Lee, S.; Rauch, J.; Kolch, W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int. J. Mol. Sci., 2020, 21(3), 1102.
[] [PMID: 32046099]
Tang, S.C.; Wu, C.H.; Lai, C.H.; Sung, W.W.; Yang, W.J.; Tang, L.C.; Hsu, C.P.; Ko, J.L. Glutathione S-transferase mu2 suppresses cancer cell metastasis in non-small cell lung cancer. Mol. Cancer Res., 2013, 11(5), 518-529.
[] [PMID: 23653452]
Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: an overview. Cancers (Basel), 2014, 6(3), 1769-1792.
[] [PMID: 25198391]
McIlwain, C.C.; Townsend, D.M.; Tew, K.D. Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene, 2006, 25(11), 1639-1648.
[] [PMID: 16550164]
Townsend, D.M.; Tew, K.D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene, 2003, 22(47), 7369-7375.
[] [PMID: 14576844]
Achkar, I.W.; Abdulrahman, N.; Al-Sulaiti, H.; Joseph, J.M.; Uddin, S.; Mraiche, F. Cisplatin based therapy: the role of the mitogen activated protein kinase signaling pathway. J. Transl. Med., 2018, 16(1), 96.
[] [PMID: 29642900]
Choueiri, T.K. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr. Opin. Investig. Drugs, 2008, 9(6), 658-671.
[PMID: 18516765]
Ditsworth, D.; Zong, W.X. NF-kappaB: key mediator of inflammation-associated cancer. Cancer Biol. Ther., 2004, 3(12), 1214-1216.
[] [PMID: 15611628]
Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer, 2013, 12, 86.
[] [PMID: 23915189]
Gilmore, T.D. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene, 2006, 25(51), 6680-6684.
[] [PMID: 17072321]
Karin, M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb. Perspect. Biol., 2009, 1(5)a000141
[] [PMID: 20066113]
DiDonato, J.A.; Mercurio, F.; Karin, M. NF-κB and the link between inflammation and cancer. Immunol. Rev., 2012, 246(1), 379-400.
[] [PMID: 22435567]
Huber, M.A.; Azoitei, N.; Baumann, B.; Grünert, S.; Sommer, A.; Pehamberger, H.; Kraut, N.; Beug, H.; Wirth, T. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest., 2004, 114(4), 569-581.
[] [PMID: 15314694]
Min, C.; Eddy, S.F.; Sherr, D.H.; Sonenshein, G.E. NF-kappaB and epithelial to mesenchymal transition of cancer. J. Cell. Biochem., 2008, 104(3), 733-744.
[] [PMID: 18253935]
Godwin, P.; Baird, A.M.; Heavey, S.; Barr, M.P.; O’Byrne, K.J.; Gately, K. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front. Oncol., 2013, 3, 120.
[] [PMID: 23720710]
Ryan, S.L.; Beard, S.; Barr, M.P.; Umezawa, K.; Heavey, S.; Godwin, P.; Gray, S.G.; Cormican, D.; Finn, S.P.; Gately, K.A.; Davies, A.M.; Thompson, E.W.; Richard, D.J.; O’Byrne, K.J.; Adams, M.N.; Baird, A.M. Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC. Lung Cancer, 2019, 135, 217-227.
[] [PMID: 31446998]
Xue, W.; Meylan, E.; Oliver, T.G.; Feldser, D.M.; Winslow, M.M.; Bronson, R.; Jacks, T. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov., 2011, 1(3), 236-247.
[] [PMID: 21874163]
Bivona, T.G.; Hieronymus, H.; Parker, J.; Chang, K.; Taron, M.; Rosell, R.; Moonsamy, P.; Dahlman, K.; Miller, V.A.; Costa, C.; Hannon, G.; Sawyers, C.L. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature, 2011, 471(7339), 523-526.
[] [PMID: 21430781]
Golks, A.; Brenner, D.; Krammer, P.H.; Lavrik, I.N. The c-FLIP-NH2 terminus (p22-FLIP) induces NF-kappaB activation. J. Exp. Med., 2006, 203(5), 1295-1305.
[] [PMID: 16682493]
Blakely, C.M.; Pazarentzos, E.; Olivas, V.; Asthana, S.; Yan, J.J.; Tan, I.; Hrustanovic, G.; Chan, E.; Lin, L.; Neel, D.S.; Newton, W.; Bobb, K.L.; Fouts, T.R.; Meshulam, J.; Gubens, M.A.; Jablons, D.M.; Johnson, J.R.; Bandyopadhyay, S.; Krogan, N.J.; Bivona, T.G. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep., 2015, 11(1), 98-110.
[] [PMID: 25843712]
Rickert, R.C.; Jellusova, J.; Miletic, A.V. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol. Rev., 2011, 244(1), 115-133.
[] [PMID: 22017435]
Kelley, M.J.; Jha, G.; Shoemaker, D.; Herndon, J.E., II; Gu, L.; Barry, W.T.; Crawford, J.; Ready, N. Phase II study of dasatinib in previously treated patients with advanced non-small cell lung cancer. Cancer Invest., 2017, 35(1), 32-35.
[] [PMID: 27911119]
Owonikoko, T.K.; Khuri, F.R. Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am. Soc. Clin. Oncol. Educ. Book, 2013.
[] [PMID: 23714559]
Yip, P.Y. Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway in non-small cell lung cancer. Transl. Lung Cancer Res., 2015, 4(2), 165-176.
[PMID: 25870799]
Fumarola, C.; Bonelli, M.A.; Petronini, P.G.; Alfieri, R.R. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem. Pharmacol., 2014, 90(3), 197-207.
[] [PMID: 24863259]
Polivka, J., Jr; Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther., 2014, 142(2), 164-175.
[] [PMID: 24333502]
Porta, C.; Paglino, C.; Mosca, A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol., 2014, 4, 64.
[] [PMID: 24782981]
Tan, A.C. Targeting the PI3K/Akt/mTOR pathway in Non-Small Cell Lung Cancer (NSCLC). Thorac. Cancer, 2020, 11(3), 511-518.
[] [PMID: 31989769]
Pérez-Ramírez, C.; Cañadas-Garre, M.; Molina, M.Á.; Faus-Dáder, M.J.; Calleja-Hernández, M.Á. PTEN and PI3K/AKT in non-small-cell lung cancer. Pharmacogenomics, 2015, 16(16), 1843-1862.
[] [PMID: 26555006]
Sato, M.; Shames, D.S.; Gazdar, A.F.; Minna, J.D. A translational view of the molecular pathogenesis of lung cancer. J. Thorac. Oncol., 2007, 2(4), 327-343.
[] [PMID: 17409807]
Sun, Z.; Wang, Z.; Liu, X.; Wang, D. New development of inhibitors targeting the PI3K/AKT/mTOR pathway in personalized treatment of non-small-cell lung cancer. Anticancer Drugs, 2015, 26(1), 1-14.
[] [PMID: 25304988]
Gadgeel, S.M.; Wozniak, A. Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. Clin. Lung Cancer, 2013, 14(4), 322-332.
[] [PMID: 23332287]
Papadimitrakopoulou, V. Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. J. Thorac. Oncol., 2012, 7(8), 1315-1326.
[] [PMID: 22648207]
Fukuda, S.; Pelus, L.M. Survivin, a cancer target with an emerging role in normal adult tissues. Mol. Cancer Ther., 2006, 5(5), 1087-1098.
[] [PMID: 16731740]
Mobahat, M.; Narendran, A.; Riabowol, K. Survivin as a preferential target for cancer therapy. Int. J. Mol. Sci., 2014, 15(2), 2494-2516.
[] [PMID: 24531137]
Groner, B.; Weiss, A. Targeting survivin in cancer: novel drug development approaches. BioDrugs, 2014, 28(1), 27-39.
[] [PMID: 23955284]
Okamoto, K.; Okamoto, I.; Hatashita, E.; Kuwata, K.; Yamaguchi, H.; Kita, A.; Yamanaka, K.; Ono, M.; Nakagawa, K. Overcoming erlotinib resistance in EGFR mutation-positive non-small cell lung cancer cells by targeting survivin. Mol. Cancer Ther., 2012, 11(1), 204-213.
[] [PMID: 22075159]
Rawlings, J.S.; Rosler, K.M.; Harrison, D.A. The JAK/STAT signaling pathway. J. Cell Sci., 2004, 117(Pt 8), 1281-1283.
[] [PMID: 15020666]
Barré, B.; Vigneron, A.; Perkins, N.; Roninson, I.B.; Gamelin, E.; Coqueret, O. The STAT3 oncogene as a predictive marker of drug resistance. Trends Mol. Med., 2007, 13(1), 4-11.
[] [PMID: 17118707]
Thomas, S.J.; Snowden, J.A.; Zeidler, M.P.; Danson, S.J. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br. J. Cancer, 2015, 113(3), 365-371.
[] [PMID: 26151455]
Yin, Z.; Zhang, Y.; Li, Y.; Lv, T.; Liu, J.; Wang, X. Prognostic significance of STAT3 expression and its correlation with chemoresistance of non-small cell lung cancer cells. Acta Histochem., 2012, 114(2), 151-158.
[] [PMID: 21549414]
Harada, D.; Takigawa, N.; Kiura, K. The role of STAT3 in non-small cell lung cancer. Cancers (Basel), 2014, 6(2), 708-722.
[] [PMID: 24675568]
Dutta, P.; Sabri, N.; Li, J.; Li, W.X. Role of STAT3 in lung cancer. JAK-STAT, 2015, 3(4)e999503
[] [PMID: 26413424]
Sun, C.Y.; Nie, J.; Huang, J.P.; Zheng, G.J.; Feng, B. Targeting STAT3 inhibition to reverse cisplatin resistance. Biomed. Pharmacother., 2019, 117109135
[] [PMID: 31226634]
Tao, L.; Huang, G.; Wang, R.; Pan, Y.; He, Z.; Chu, X.; Song, H.; Chen, L. Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci. Rep., 2016, 6, 38408.
[] [PMID: 27922075]
Zahreddine, H.; Borden, K.L.B. Mechanisms and insights into drug resistance in cancer. Front. Pharmacol., 2013, 4, 28.
[] [PMID: 23504227]
Koo, K.H.; Kim, H.; Bae, Y.K.; Kim, K.; Park, B.K.; Lee, C.H.; Kim, Y.N. Salinomycin induces cell death via inactivation of STAT3 and downregulation of Skp2. Cell Death Dis., 2013, 4(6)e693
[] [PMID: 23807222]
Zhuang, L.; Lee, C.S.; Scolyer, R.A.; McCarthy, S.W.; Zhang, X.D.; Thompson, J.F.; Hersey, P. Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod. Pathol., 2007, 20(4), 416-426.
[] [PMID: 17384650]
Al Zaid Siddiquee, K.; Turkson, J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res., 2008, 18(2), 254-267.
[] [PMID: 18227858]
Wu, K.; Chang, Q.; Lu, Y.; Qiu, P.; Chen, B.; Thakur, C.; Sun, J.; Li, L.; Kowluru, A.; Chen, F. Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells. Oncotarget, 2013, 4(12), 2430-2438.
[] [PMID: 24280348]
Ostojic, A.; Vrhovac, R.; Verstovsek, S. Ruxolitinib for the treatment of myelofibrosis: its clinical potential. Ther. Clin. Risk Manag., 2012, 8, 95-103.
[PMID: 22399854]
Song, L.; Rawal, B.; Nemeth, J.A.; Haura, E.B. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol. Cancer Ther., 2011, 10(3), 481-494.
[] [PMID: 21216930]
Sim, E.H.; Yang, I.A.; Wood-Baker, R.; Bowman, R.V.; Fong, K.M. Gefitinib for advanced non-small cell lung cancer. Cochrane Database Syst. Rev., 2018, 1(1)CD006847
[] [PMID: 29336009]
Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol., 2012, 4(5), 4.
[] [PMID: 22438566]
He, B.; Jablons, D.M. Wnt signaling in stem cells and lung cancer. Ernst Schering Found Symp. Proc, 2006, pp. 27-58.
He, B.; Barg, R.N.; You, L.; Xu, Z.; Reguart, N.; Mikami, I.; Batra, S.; Rosell, R.; Jablons, D.M. Wnt signaling in stem cells and non-small-cell lung cancer. Clin. Lung Cancer, 2005, 7(1), 54-60.
[] [PMID: 16098245]
Pongracz, J.E.; Stockley, R.A. Wnt signalling in lung development and diseases. Respir. Res., 2006, 7, 15.
[] [PMID: 16438732]
Wang, Z.; Li, Y.; Ahmad, A.; Azmi, A.S.; Banerjee, S.; Kong, D.; Sarkar, F.H. Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim. Biophys. Acta, 2010, 1806(2), 258-267.
[PMID: 20600632]
Anastas, J.N.; Moon, R.T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer, 2013, 13(1), 11-26.
[] [PMID: 23258168]
Takebe, N.; Miele, L.; Harris, P.J.; Jeong, W.; Bando, H.; Kahn, M.; Yang, S.X.; Ivy, S.P. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol., 2015, 12(8), 445-464.
[] [PMID: 25850553]
Peng, Y.; Zhang, X.; Feng, X.; Fan, X.; Jin, Z. The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer. Oncotarget, 2017, 8(8), 14089-14106.
[] [PMID: 27793042]
Zhang, H.; Jing, X.; Wu, X.; Hu, J.; Zhang, X.; Wang, X.; Su, P.; Li, W.; Zhou, G. Suppression of multidrug resistance by rosiglitazone treatment in human ovarian cancer cells through downregulation of FZD1 and MDR1 genes. Anticancer Drugs, 2015, 26(7), 706-715.
[] [PMID: 26053275]
Zhang, H.; Zhang, X.; Wu, X.; Li, W.; Su, P.; Cheng, H.; Xiang, L.; Gao, P.; Zhou, G. Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway. Cancer Lett., 2012, 323(1), 106-113.
[] [PMID: 22484497]
Shen, D.W.; Pouliot, L.M.; Hall, M.D.; Gottesman, M.M. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol. Rev., 2012, 64(3), 706-721.
[] [PMID: 22659329]
Pai, S.G.; Carneiro, B.A.; Mota, J.M.; Costa, R.; Leite, C.A.; Barroso-Sousa, R.; Kaplan, J.B.; Chae, Y.K.; Giles, F.J. Wnt/beta-catenin pathway: modulating anticancer immune response. J. Hematol. Oncol., 2017, 10(1), 101.
[] [PMID: 28476164]
Yang, J.; Chen, J.; He, J.; Li, J.; Shi, J.; Cho, W.C.; Liu, X. Wnt signaling as potential therapeutic target in lung cancer. Expert Opin. Ther. Targets, 2016, 20(8), 999-1015.
[] [PMID: 26882052]
Martin-Orozco, E.; Sanchez-Fernandez, A.; Ortiz-Parra, I.; Ayala-San Nicolas, M. WNT Signaling in tumors: the way to evade drugs and immunity. Front. Immunol., 2019, 10, 2854.
[] [PMID: 31921125]
Akiri, G.; Cherian, M.M.; Vijayakumar, S.; Liu, G.; Bafico, A.; Aaronson, S.A. Wnt pathway aberrations including autocrine Wnt activation occur at high frequency in human non-small-cell lung carcinoma. Oncogene, 2009, 28(21), 2163-2172.
[] [PMID: 19377513]
Gao, Y.; Liu, Z.; Zhang, X.; He, J.; Pan, Y.; Hao, F.; Xie, L.; Li, Q.; Qiu, X.; Wang, E. Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells. Cancer Lett., 2013, 336(1), 231-239.
[] [PMID: 23673211]
Stewart, D.J. Wnt signaling pathway in non-small cell lung cancer. J. Natl. Cancer Inst., 2014, 106(1)djt356
[] [PMID: 24309006]
Song, Z.; Wang, H.; Zhang, S. Negative regulators of Wnt signaling in non-small cell lung cancer: theoretical basis and therapeutic potency. Biomed. Pharmacother., 2019, 118109336
[] [PMID: 31545260]
Chiu, Y.H.; Hsu, S.H.; Hsu, H.W.; Huang, K.C.; Liu, W.; Wu, C.Y.; Huang, W.P.; Chen, J.Y.; Chen, B.H.; Chiu, C.C. Human non small cell lung cancer cells can be sensitized to camptothecin by modulating autophagy. Int. J. Oncol., 2018, 53(5), 1967-1979.
[] [PMID: 30106130]

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