Intrinsic resistance to tyrosine kinase inhibitor (TKI) drugs is limiting the progress of targeted cancer therapies. The efficacy of TKIs relies on their inhibition of oncogenic signaling but also on the induction of apoptosis in cancer cells, driven by activation of pro-apoptotic BIM proteins. The authors identify a germline BIM polymorphism common in East Asian individuals that switches BIM splicing, eliminating the BH3 domain responsible for apoptosis induction. The polymorphism provides resistance to TKIs, such as BCR-ABL inhibitors in chronic myeloid leukemia and EGFR inhibitors in non–small-cell lung cancer samples, and drug sensitivity can be reinstated by addition of BH3-mimetic drugs. The polymorphism predicts treatment responses and outcome in East Asian patients with leukemia and lung cancer and could provide useful guidance for therapeutic implementation.
- King Pan Ng
- Axel M Hillmer
- S Tiong Ong
