A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer.
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.
Ng, KP; Hillmer, AM; Chuah, CTH; Juan, WC; Ko, TK; Teo, ASM; Ariyaratne, PN; Takahashi, N; Sawada, K; Fei, Y; Soh, S; Lee, WH; Huang, JWJ; Allen, JC; Woo, XY; Nagarajan, N; Kumar, V; Thalamuthu, A; Poh, WT; Ang, AL; Mya, HT; How, GF; Yang, LY; Koh, LP; Chowbay, B; Chang, C-T; Nadarajan, VS; Chng, WJ; Than, H; Lim, LC; Goh, YT; Zhang, S; Poh, D; Tan, P; Seet, J-E; Ang, M-K; Chau, N-M; Ng, Q-S; Tan, DSW; Soda, M; Isobe, K; Nöthen, MM; Wong, TY; Shahab, A; Ruan, X; Cacheux-Rataboul, V; Sung, W-K; Tan, EH; Yatabe, Y; Mano, H; Soo, RA; Chin, TM; Lim, W-T; Ruan, Y; Ong, ST
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