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Cell Rep. 2014 Apr 10;7(1):86-93. doi: 10.1016/j.celrep.2014.02.045. Epub 2014 Mar 27.

Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3.

Author information

1
Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
2
Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
3
Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
4
Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
5
Department of Pulmonary Diseases, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
6
Department of Pathology, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
7
Department of Oncology, University of Torino, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
8
Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy; FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy. Electronic address: alberto.bardelli@ircc.it.
9
Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.

Abstract

There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.

PMID:
24685132
DOI:
10.1016/j.celrep.2014.02.045
[Indexed for MEDLINE]
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