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Cell Rep. 2014 Sep 11;8(5):1475-83. doi: 10.1016/j.celrep.2014.07.033. Epub 2014 Sep 4.

RAF suppression synergizes with MEK inhibition in KRAS mutant cancer cells.

Author information

1
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.
2
Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
3
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.
4
Candiolo Cancer Institute-FPO, IRCCS, Str prov 142 Km 3.95, Candiolo, 10060 Torino, Italy.
5
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.
6
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.

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.

PMID:
25199829
DOI:
10.1016/j.celrep.2014.07.033
[Indexed for MEDLINE]
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