A genome-wide CRISPR screen identifies FBXO42 involvement in resistance towards MEK inhibition in NRAS mutant melanoma.

A genome-wide CRISPR screen identifies FBXO42 involvement in resistance towards MEK inhibition in NRAS mutant melanoma. Pigment Cell Melanoma Res. 2019 Sep 24;: Authors: Nagler A, Vredevoogd DW, Alon M, Cheng PF, Trabish S, Kalaora S, Arafeh R, Goldin V, Levesque MP, Peeper DS, Samuels Y Abstract NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS mutant melanoma cells. Our findings thus show a new pathway involved in NR...
Source: Pigment Cell and Melanoma Research - Category: Cytology Authors: Tags: Pigment Cell Melanoma Res Source Type: research