title: MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents.
abstract: Targeted therapies for cancer are inherently limited by the inevitable recurrence of resistant disease after initial responses. To define early molecular changes within residual tumor cells that persist after treatment, we analyzed drug-sensitive lung adenocarcinoma cell lines exposed to reversible or irreversible epidermal growth factor receptor (EGFR) inhibitors, alone or in combination with MET-kinase inhibitors, to characterize the adaptive response that engenders drug resistance. Tumor cells displaying early resistance exhibited dependence on MET-independent activation of BCL-2/BCL-XL survival signaling. Further, such cells displayed a quiescence-like state associated with greatly retarded cell proliferation and cytoskeletal functions that were readily reversed after withdrawal of targeted inhibitors. Findings were validated in a xenograft model, showing BCL-2 induction and p-STAT3[Y705] activation within the residual tumor cells surviving the initial antitumor response to targeted therapies. Disrupting the mitochondrial BCL-2/BCL-XL antiapoptotic machinery in early survivor cells using BCL-2 Homology Domain 3 (BH3) mimetic agents such as ABT-737, or by dual RNAi-mediated knockdown of BCL-2/BCL-XL, was sufficient to eradicate the early-resistant lung-tumor-cells evading targeted inhibitors. Similarly, in a xenograft model the preemptive cotreatment of lung tumor cells with an EGFR inhibitor and a BH3 mimetic eradicated early TKI-resistant evaders and ultimately achieved a more durable response with prolonged remission. Our findings prompt prospective clinical investigations using BH3-mimetics combined with targeted receptor kinase inhibitors to optimize and improve clinical outcomes in lung-cancer treatment.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Fan
authors.forename: Zhe
authors.initials: Z
authors.lastname: Tang
authors.forename: Lihong
authors.initials: L
authors.lastname: Yin
authors.forename: Bei
authors.initials: B
authors.lastname: Morrison
authors.forename: Said
authors.initials: S
authors.lastname: Hafez-Khayyata
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.forename: Honglian
authors.initials: H
authors.lastname: Huang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bagai
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Adam
authors.initials: A
authors.lastname: Kresak
authors.forename: Scott
authors.initials: S
authors.lastname: Howell
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.forename: Henry
authors.initials: H
authors.lastname: Koon
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Ma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D007211:Indoles; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D051020:bcl-X Protein; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met