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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.
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.
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.
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
ISSN: 10788956
DOI: 10.1038/nm.2713
Appears in Collections:Staff Publications

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