A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

• Published in: Nature medicine Vol. 18; no. 4; pp. 521 - 528
• Main Authors: Ng, King Pan, Hillmer, Axel M, Chuah, Charles T H, Juan, Wen Chun, Ko, Tun Kiat, Teo, Audrey S M, Ariyaratne, Pramila N, Takahashi, Naoto, Sawada, Kenichi, Fei, Yao, Soh, Sheila, Lee, Wah Heng, Huang, John W J, Allen, John C, Woo, Xing Yi, Nagarajan, Niranjan, Kumar, Vikrant, Thalamuthu, Anbupalam, Poh, Wan Ting, Ang, Ai Leen, Mya, Hae Tha, How, Gee Fung, Yang, Li Yi, Koh, Liang Piu, Chowbay, Balram, Chang, Chia-Tien, Nadarajan, Veera S, Chng, Wee Joo, Than, Hein, Lim, Lay Cheng, Goh, Yeow Tee, Zhang, Shenli, Poh, Dianne, Tan, Patrick, Seet, Ju-Ee, Ang, Mei-Kim, Chau, Noan-Minh, Ng, Quan-Sing, Tan, Daniel S W, Soda, Manabu, Isobe, Kazutoshi, Nöthen, Markus M, Wong, Tien Y, Shahab, Atif, Ruan, Xiaoan, Cacheux-Rataboul, Valère, Sung, Wing-Kin, Tan, Eng Huat, Yatabe, Yasushi, Mano, Hiroyuki, Soo, Ross A, Chin, Tan Min, Lim, Wan-Teck, Ruan, Yijun, Ong, S Tiong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2012; Nature Publishing Group
• Subjects: 631/154/309/436/434; 631/208/457/649/2157; 692/699/67/1990/283/1896; Adult; Aged; Aged, 80 and over; Annexins - metabolism; Antimitotic agents; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Cohort Studies; Deoxyribonucleic acid; DNA; Dosage and administration; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme-Linked Immunosorbent Assay - methods; Exons - genetics; Female; Follow-Up Studies; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Frequency; Genetic aspects; Genetic polymorphisms; Genotype; Heterogeneity; Humans; Infectious Diseases; Inhibitor drugs; Inhibitors; International Cooperation; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lymphoma; Male; Membrane Proteins - genetics; Metabolic Diseases; Middle Aged; Molecular Medicine; Mutation; Neurosciences; Physiological aspects; Polymorphism; Polymorphism, Genetic - genetics; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Kinase Inhibitors - pharmacology; Protein tyrosine kinase; Proto-Oncogene Proteins - genetics; Receptor, Epidermal Growth Factor - genetics; RNA, Small Interfering - metabolism; Sequence Deletion - genetics; Statistics, Nonparametric; Transfection; Tumor proteins; Japan
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2713

Intrinsic resistance to tyrosine kinase inhibitor (TKI) drugs is limiting the progress of targeted cancer therapies. The efficacy of TKIs relies on their inhibition of oncogenic signaling but also on the induction of apoptosis in cancer cells, driven by activation of pro-apoptotic BIM proteins. The authors identify a germline BIM polymorphism common in East Asian individuals that switches BIM splicing, eliminating the BH3 domain responsible for apoptosis induction. The polymorphism provides resistance to TKIs, such as BCR-ABL inhibitors in chronic myeloid leukemia and EGFR inhibitors in non–small-cell lung cancer samples, and drug sensitivity can be reinstated by addition of BH3-mimetic drugs. The polymorphism predicts treatment responses and outcome in East Asian patients with leukemia and lung cancer and could provide useful guidance for therapeutic implementation. Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor–mutated non–small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism ( P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM -polymorphism–associated TKI resistance.