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

Autor:	Faber AC; Massachusetts General Hospital Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129, USA., Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy SR, Pollack SF, Song Y, Muzikansky A, Lifshits E, Roberge S, Coffman EJ, Benes CH, Gómez HL, Baselga J, Arteaga CL, Rivera MN, Dias-Santagata D, Jain RK, Engelman JA
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2011 Sep; Vol. 1 (4), pp. 352-65. Date of Electronic Publication: 2011 Jul 22.
DOI:	10.1158/2159-8290.CD-11-0106
Abstrakt:	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.)
Databáze:	MEDLINE
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