title: Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3.
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.
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Chong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Sebastijan
authors.initials: S
authors.lastname: Hobor
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.affiliation: 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.
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottino
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Prahallad
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Wipawadee
authors.initials: W
authors.lastname: Grernrum
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Tzani
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Department of Pathology, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Pasi
authors.initials: P
authors.lastname: Halonen
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Department of Oncology, University of Torino, Strada Provinciale 142 km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: 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.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.affiliation: 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.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D018631:ras Proteins; C117307:KRAS protein, human; C512478:EGFR protein, human; C581292:ERBB3 protein, human