IKKα kinase regulates the DNA damage response and drives chemo-resistance in cancer

Abstract

Phosphorylated IKKalpha(p45) is a nuclear active form of the IKKalpha kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-¿B signaling. Insights into the sources of IKKalpha(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKalpha(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKalpha activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKalpha or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKalpha kinases in the DDR and reveal a combination strategy for cancer treatment. ; This work was funded by grants from Instituto de Salud Carlos III FEDER (PIE15/00008 and PI16/00437), Generalitat de Catalunya 2017SGR135, and the "Xarxa de Bancs de Tumors" sponsored by Pla Director d'Oncologia de Catalunya (XBTC). C.C. is supported by FPI BES-2014-068451 and the EMBO Short-Term Fellowship (na7084). P.M. is supported by funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement #702430. The Boulton lab is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048). S.J.B. is funded by European Research Council (ERC) Advanced Investigator Grants (TelMetab) and a Wellcome Trust Senior Investigator Grant. The Centre de Regulació Genòmica/Universitat Pompeu Fabra Proteomics Unit is part of the "Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)" supported by grant PT13/0001 of Instituto de Salud Carlos III from the Spanish government and "Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya" (2014SGR678). We acknowledge support from the Spanish Ministry of Economy and Competitiveness and "Centro de Excelencia Severo Ochoa 2013-2017" (SEV-2012-0208).