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

Chong Sun; Sebastijan Hobor; Andrea Bertotti; Davide Zecchin; Sidong Huang; Francesco Galimi; Francesca Cottino; Anirudh Prahallad; Wipawadee Grernrum; Anna Tzani; Andreas Schlicker; Lodewyk F A Wessels; Egbert F Smit; Erik Thunnissen; Pasi Halonen; Cor Lieftink; Roderick L Beijersbergen; Federica Di Nicolantonio; Alberto Bardelli; Livio Trusolino; Rene Bernards

doi:10.1016/j.celrep.2014.02.045

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

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

Authors

Chong Sun¹, Sebastijan Hobor², Andrea Bertotti³, Davide Zecchin³, Sidong Huang⁴, Francesco Galimi³, Francesca Cottino², Anirudh Prahallad¹, Wipawadee Grernrum¹, Anna Tzani¹, Andreas Schlicker¹, Lodewyk F A Wessels¹, Egbert F Smit⁵, Erik Thunnissen⁶, Pasi Halonen¹, Cor Lieftink¹, Roderick L Beijersbergen¹, Federica Di Nicolantonio⁷, Alberto Bardelli⁸, Livio Trusolino³, Rene Bernards⁹

Affiliations

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.

PMID: 24685132
DOI: 10.1016/j.celrep.2014.02.045

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Cell Line, Tumor
Colonic Neoplasms / drug therapy
Colonic Neoplasms / enzymology*
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Drug Synergism
ErbB Receptors / antagonists & inhibitors
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / enzymology*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Mice
Mice, Nude
Mutation
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins p21(ras)
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / metabolism
Receptor, ErbB-3 / biosynthesis*
Receptor, ErbB-3 / genetics
Receptor, ErbB-3 / metabolism
Xenograft Model Antitumor Assays
ras Proteins / genetics*
ras Proteins / metabolism

Substances

KRAS protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins
RNA, Small Interfering
EGFR protein, human
ERBB3 protein, human
ErbB Receptors
Receptor, ErbB-2
Receptor, ErbB-3
MAP Kinase Kinase Kinases
Proto-Oncogene Proteins p21(ras)
ras Proteins