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Cancer Res. 2014 Jun 1;74(11):3146-56. doi: 10.1158/0008-5472.CAN-13-3728. Epub 2014 Mar 27.

Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers.

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1
Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
2
Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
3
Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts jengelman@partners.org.

Abstract

Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy.

PMID:
24675361
PMCID:
PMC4046322
DOI:
10.1158/0008-5472.CAN-13-3728
[Indexed for MEDLINE]
Free PMC Article

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