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Cancer Discov. 2011 Sep;1(4):352-65. doi: 10.1158/2159-8290.CD-11-0106. Epub 2011 Jul 22.

BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors.

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  • 1Massachusetts General Hospital Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129, USA.

Abstract

Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.

©2011 AACR.

KEYWORDS:

BIM; EGFR; HER2; apoptosis; oncogene addiction

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PMID:
22145099
[PubMed - indexed for MEDLINE]
PMCID:
PMC3229203
Free PMC Article

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