CRAF mutations in lung cancer can be oncogenic and predict sensitivity to combined type II RAF and MEK inhibition

Amir Noeparast, Philippe Giron, Alfiah Noor, Rajendra Bahadur Shahi, Sylvia De Brakeleer, Carolien Eggermont, Hugo Vandenplas, Bram Boeckx, Diether Lambrechts, Jacques De Grève, Erik Teugels

Onderzoeksoutput: Articlepeer review

10 Citaten (Scopus)


Two out of 41 non-small cell lung cancer patients enrolled in a clinical study were found with a somatic CRAF mutation in their tumor, namely CRAFP261A and CRAFP207S. To our knowledge, both mutations are novel in lung cancer and CRAFP261A has not been previously reported in cancer. Expression of CRAFP261A in HEK293T cells and BEAS-2B lung epithelial cells led to increased ERK pathway activation in a dimer-dependent manner, accompanied with loss of CRAF phosphorylation at the negative regulatory S259 residue. Moreover, stable expression of CRAFP261A in mouse embryonic fibroblasts and BEAS-2B cells led to anchorage-independent growth. Consistent with a previous report, we could not observe a gain-of-function with CRAFP207S. Type II but not type I RAF inhibitors suppressed the CRAFP261A-induced ERK pathway activity in BEAS-2B cells, and combinatorial treatment with type II RAF inhibitors and a MEK inhibitor led to a stronger ERK pathway inhibition and growth arrest. Our findings suggest that the acquisition of a CRAFP261A mutation can provide oncogenic properties to cells, and that such cells are sensitive to combined MEK and type II RAF inhibitors. CRAF mutations should be diagnostically and therapeutically explored in lung and perhaps other cancers.

Originele taal-2English
Pagina's (van-tot)5933-5941
Aantal pagina's9
Nummer van het tijdschrift31
StatusPublished - aug 2019


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