A deletion polymorphism in the BIM gene causes an inferior TKI response.
Major finding: A deletion polymorphism in the BIM gene causes an inferior TKI response.
Mechanism: Alternative splicing generates a BIM isoform that lacks the BH3 domain.
Impact: BH3 mimetics may be used to overcome TKI resistance in a subset of patients.
Although the majority of patients with malignancies driven by oncogenic kinases, such as chronic myeloid leukemia (CML) and epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC), respond to treatment with tyrosine kinase inhibitors (TKI), the duration and extent of these clinical responses remain heterogeneous. Recent studies have shown that expression of BIM, a proapoptotic BH3-only protein that belongs to the BCL2 family, is necessary for TKI-induced apoptosis in kinase-driven malignancies. In a search for genetic modifiers that alter the apoptotic response to TKIs, Ng and colleagues identified a common deletion polymorphism within intron 2 of the BIM gene that mediates intrinsic resistance. The 2,903-bp genomic deletion, found to be carried specifically in individuals of East Asian descent, generates an alternatively spliced BIM isoform lacking the exon 4–encoded BH3 domain that is required for apoptosis. Consistent with this finding, polymorphism-containing CML and EGFR-mutant NSCLC cells exposed to TKIs showed a decrease in apoptotic signaling, and introduction of the deletion polymorphism into TKI-sensitive cells was sufficient to render them resistant to treatment. Importantly, the addition of BH3-mimetic drugs that functionally mimic BH3-only proteins restored apoptotic signaling and cell death in both cases. The presence of the polymorphism also predicted an inferior clinical TKI response in patients with CML and EGFR-mutant NSCLC. These findings not only establish BIM polymorphism as a specific mechanism of intrinsic resistance to TKIs but also more generally suggest that germline polymorphisms, in addition to somatic mutations, may affect clinical outcome in patients treated with targeted therapies.
Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 2012;18:521–8.
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