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

作者：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 Jr; 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

来源：Nature Medicine, 2012, 18(4): 521-528.

DOI：10.1038/nm.2713

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%26apos;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.

• 出版日期2012-4