title: RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells.
abstract: KRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA) screening of 37 KRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition. An unbiased kinome short hairpin RNA (shRNA)-based screen confirmed this synthetic lethal interaction in colorectal as well as in lung cancer cells bearing KRAS mutations. Compounds targeting RAF kinases can reverse resistance to the MEK inhibitor selumetinib. MEK inhibition induces RAS activation and BRAF-RAF1 dimerization and sustains MEK-ERK signaling, which is responsible for intrinsic resistance to selumetinib. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis. Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in KRAS mutant tumors.
authors.affiliation: Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.affiliation: Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
authors.forename: Chong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lazzari
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
authors.forename: Wipawadee
authors.initials: W
authors.lastname: Grernrum
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy. Electronic address: federica.dinicolantonio@unito.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Department of Oncology, University of Torino, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy. Electronic address: alberto.bardelli@unito.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins