Journal
CELL REPORTS
Volume 8, Issue 5, Pages 1475-1483Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.033
Keywords
-
Categories
Funding
- European Community's Seventh Framework Programme [259015 COLTHERES]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) IG [12812]
- AIRC MFAG [11349]
- MIUR-Fondazione Piemontese per la Ricerca sul Cancro-ONLUS
- AIRC 2010 Special Program Molecular Clinical Oncology 5 per mille, [9970]
- Ministero della Salute-FPRC onlus
- Ministero della Salute
- Ministero dell'Istruzione, dell'Universitae della Ricerca, progetto PRIN
- Progetti di Ateneo
- Universita di Torino [ORTO11RKTW]
- European Research Council (ERC)
- Dutch Cancer Society (KWF)
- Netherlands Organization for Scientific Research (NWO)
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available