Kinase-independent role for CRAF-driving tumour radioresistance via CHK2

Sunil J. Advani, Maria Fernanda Camargo, Laetitia Seguin, Ainhoa Mielgo, Sudarshan Anand, Angel M. Hicks, Joseph Aguilera, Aleksandra Franovic, Sara M. Weis and David A. Cheresh ()
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Sunil J. Advani: University of California, San Diego
Maria Fernanda Camargo: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
Laetitia Seguin: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
Ainhoa Mielgo: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
Sudarshan Anand: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
Angel M. Hicks: University of California, San Diego
Joseph Aguilera: University of California, San Diego
Aleksandra Franovic: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
Sara M. Weis: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA
David A. Cheresh: University of California, San Diego, 3855 Health Science Drive, La Jolla, California 92037, USA

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract Although oncology therapy regimens commonly include radiation and genotoxic drugs, tumour cells typically develop resistance to these interventions. Here we report that treatment of tumours with ionizing radiation or genotoxic drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation of CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism of DNA repair and therapeutic resistance. CRAF pS338 recruits CHK2, a cell cycle checkpoint kinase involved in DNA repair, and promotes CHK2 phosphorylation/activation to enhance the tumour cell DNA damage response. Accordingly, a phospho-mimetic mutant of CRAF (S338D) is sufficient to induce the CRAF/CHK2 association enhancing tumour radioresistance, while an allosteric CRAF inhibitor sensitizes tumour cells to ionizing radiation or genotoxic drugs. Our findings establish a role for CRAF in the DNA damage response that is independent from its canonical function as a kinase.

Date: 2015
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DOI: 10.1038/ncomms9154

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