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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • March 18, 2012

Published In

Volume / Issue

  • 18 / 4

Start / End Page

  • 521 - 528

PubMed ID

  • 22426421

Pubmed Central ID

  • 22426421

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm.2713

Language

  • eng