RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells

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)...

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Vydané v:Cell reports (Cambridge) Ročník 8; číslo 5; s. 1475 - 1483
Hlavní autori: Lamba, Simona, Russo, Mariangela, Sun, Chong, Lazzari, Luca, Cancelliere, Carlotta, Grernrum, Wipawadee, Lieftink, Cor, Bernards, Rene, Di Nicolantonio, Federica, Bardelli, Alberto
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 11.09.2014
Elsevier
Predmet:
Antineoplastic Agents - pharmacology
Apoptosis
Benzimidazoles - pharmacology
Cell Line, Tumor
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - genetics
Mitogen-Activated Protein Kinase Kinases - metabolism
Mutation
Protein Kinase Inhibitors - pharmacology
Protein Multimerization
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins p21(ras)
raf Kinases - antagonists & inhibitors
raf Kinases - genetics
raf Kinases - metabolism
ras Proteins - genetics
ras Proteins - metabolism
ISSN:2211-1247, 2211-1247
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Shrnutí: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. [Display omitted] •MEK inhibition induces BRAF-RAF1 heterodimerization in KRAS mutant tumor cells•RAF1 and MEK inhibition is synthetic lethal in KRAS mutant colon and lung tumors•Concomitant RAF-MEK inhibition leads to ERK suppression and apoptosis Lamba et al. found that RAF1 suppression is synthetic lethal with MEK inhibition in KRAS mutant colorectal and lung tumors, for which no effective therapies are available. Concomitant inhibition of RAF1 and MEK induces prolonged mitogen-activated protein kinase pathway suppression and apoptosis. These data underlie the relevance of developing combinatorial regimens of drugs targeting both RAF and MEK in KRAS mutant tumors.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2014.07.033