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, David A. Cheresh

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number8154
JournalNature Communications
Volume6
DOIs
StatePublished - Sep 3 2015
Externally publishedYes

Fingerprint

Tumors
Phosphotransferases
tumors
deoxyribonucleic acid
Cells
phosphorylation
Phosphorylation
drugs
DNA
Ionizing radiation
Neoplasms
Ionizing Radiation
DNA Repair
ionizing radiation
DNA Damage
Repair
p21-Activated Kinases
Pharmaceutical Preparations
damage
Oncology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Advani, S. J., Camargo, M. F., Seguin, L., Mielgo, A., Anand, S., Hicks, A. M., ... Cheresh, D. A. (2015). Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nature Communications, 6, [8154]. https://doi.org/10.1038/ncomms9154

Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. / Advani, Sunil J.; Camargo, Maria Fernanda; Seguin, Laetitia; Mielgo, Ainhoa; Anand, Sudarshan; Hicks, Angel M.; Aguilera, Joseph; Franovic, Aleksandra; Weis, Sara M.; Cheresh, David A.

In: Nature Communications, Vol. 6, 8154, 03.09.2015.

Research output: Contribution to journalArticle

Advani, SJ, Camargo, MF, Seguin, L, Mielgo, A, Anand, S, Hicks, AM, Aguilera, J, Franovic, A, Weis, SM & Cheresh, DA 2015, 'Kinase-independent role for CRAF-driving tumour radioresistance via CHK2', Nature Communications, vol. 6, 8154. https://doi.org/10.1038/ncomms9154
Advani, Sunil J. ; Camargo, Maria Fernanda ; Seguin, Laetitia ; Mielgo, Ainhoa ; Anand, Sudarshan ; Hicks, Angel M. ; Aguilera, Joseph ; Franovic, Aleksandra ; Weis, Sara M. ; Cheresh, David A. / Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. In: Nature Communications. 2015 ; Vol. 6.
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