Home > Articles > Published articles > IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer |
Date: | 2019 |
Abstract: | Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(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 IKKα 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, IKKα 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 IKKα kinases in the DDR and reveal a combination strategy for cancer treatment. Colomer et al. discover that IKKα kinase contributes to the chemo- and radio-resistance of cancer cells by facilitating ATM activation and DNA repair. BRAF inhibitors prevent damage-induced IKKα activation, leading to the attenuation of ATM signaling and DNA repair. IKKα depletion or BRAF inhibitors combined with 5-FU and irinotecan synergistically enhance the killing of patient-derived xenograft tumors. |
Grants: | Instituto de Salud Carlos III PIE15-00008 Instituto de Salud Carlos III PI16-00437 Instituto de Salud Carlos III PT13-0001 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR135 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR678 Ministerio de Economía y Competitividad BES-2014-068451 Ministerio de Economía y Competitividad SEV-2012-0208 European Commission 702430 |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | IKK ; BRAF ; Combination therapy ; Cancer treatment ; ATM ; Phosphorylation ; DNA-damage Repair ; Therapy resistance ; Patient-derived organoids ; Ortho-xenografts |
Published in: | Molecular Cell, Vol. 75 (august 2019) , p. 669-682.e5, ISSN 1097-4164 |
20 p, 6.8 MB |