A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.
СтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.