IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer

Summary

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.

Graphical Abstract

Highlights

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  IKKα kinase is activated by BRAF-TAK1-p38-MAPK in response to DNA damage

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  Loss of IKKα or BRAF attenuates ATM signaling and compromises DNA repair

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  Loss of IKKα or BRAF in combination with DNA damage potentiates tumor eradication

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  Combination treatment of patient-derived tumors prolongs survival in mice

Abstract

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.