Kinase-independent role for CRAF-driving tumour radioresistance via CHK2
作者： Sunil J. Advani , Maria Fernanda Camargo , Laetitia Seguin , Ainhoa Mielgo , Sudarshan Anand
DOI: 10.1038/NCOMMS9154
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摘要: 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 or drugs drives p21-activated kinase 1 (PAK1)-mediated phosphorylation CRAF on Serine 338 (pS338) triggering a kinase-independent mechanism DNA repair therapeutic resistance. pS338 recruits CHK2, cell cycle checkpoint involved in repair, promotes CHK2 phosphorylation/activation enhance the damage response. Accordingly, phospho-mimetic mutant (S338D) is sufficient induce CRAF/CHK2 association enhancing radioresistance, while an allosteric inhibitor sensitizes drugs. Our findings establish role for response independent from its canonical function as kinase.
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