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|Title:||A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer||Authors:||Ng, K.P.
Allen Jr., J.C.
|Issue Date:||Apr-2012||Citation:||Ng, K.P., Hillmer, A.M., Chuah, C.T.H., Juan, W.C., Ko, T.K., Teo, A.S.M., Ariyaratne, P.N., Takahashi, N., Sawada, K., Fei, Y., Soh, S., Lee, W.H., Huang, J.W.J., Allen Jr., J.C., Woo, X.Y., Nagarajan, N., Kumar, V., Thalamuthu, A., Poh, W.T., Ang, A.L., Mya, H.T., How, G.F., Yang, L.Y., Koh, L.P., Chowbay, B., Chang, C.-T., Nadarajan, V.S., Chng, W.J., Than, H., Lim, L.C., Goh, Y.T., Zhang, S., Poh, D., Tan, P., Seet, J.-E., Ang, M.-K., Chau, N.-M., Ng, Q.-S., Tan, D.S.W., Soda, M., Isobe, K., Nöthen, M.M., Wong, T.Y., Shahab, A., Ruan, X., Cacheux-Rataboul, V., Sung, W.-K., Tan, E.H., Yatabe, Y., Mano, H., Soo, R.A., Chin, T.M., Lim, W.-T., Ruan, Y., Ong, S.T. (2012-04). A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 18 (4) : 521-528. ScholarBank@NUS Repository. https://doi.org/10.1038/nm.2713||Abstract:||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. © 2012 Nature America, Inc. All rights reserved.||Source Title:||Nature Medicine||URI:||http://scholarbank.nus.edu.sg/handle/10635/53381||ISSN:||10788956||DOI:||10.1038/nm.2713|
|Appears in Collections:||Staff Publications|
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