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

Carlota Colomer1, Pol Margalef2, Alberto Villanueva3

  • 1Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain.

Molecular Cell
|July 15, 2019
PubMed

Insights

Phosphorylated IKKα (p45) kinase, activated by DNA damage via BRAF-TAK1-p38-MAPK, is crucial for DNA repair and ATM activation. Inhibiting BRAF or IKKα enhances cancer therapy effectiveness.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • DNA Damage Response

Background:

  • Phosphorylated IKKα (p45) is a nuclear kinase promoting tumor growth independently of NF-κB.
  • The activation pathways and nuclear substrates of IKKα(p45) are not fully understood.

Purpose of the Study:

  • To elucidate the activation mechanism of IKKα(p45) upon DNA damage.
  • To investigate the role of IKKα(p45) in DNA repair pathways.
  • To explore the therapeutic potential of targeting BRAF and IKKα in cancer treatment.

Main Methods:

  • Investigated IKKα(p45) activation in response to DNA damage.
  • Utilized genetic inhibition of BRAF and IKKα.
  • Assessed DNA repair protein phosphorylation and recruitment to DNA lesions.
  • Evaluated tumor growth and therapeutic response in vivo models.

Main Results:

  • IKKα(p45) is activated by DNA damage, dependent on BRAF-TAK1-p38-MAPK, and required for ATM activation and DNA repair.
  • BRAF or IKKα inhibition reduced phosphorylation of ATM, Chk1, MDC1, Kap1, and 53BP1.
  • Inhibition compromised 53BP1 and RIF1 recruitment to DNA lesions and 53BP1-dependent telomere fusion.
  • Combined inhibition of IKKα or BRAF with chemotherapy synergistically eradicated tumors in vivo.

Conclusions:

  • BRAF and IKKα kinases are implicated in the DNA damage response (DDR).
  • Targeting BRAF or IKKα represents a promising combination strategy for enhancing cancer chemotherapy.
  • This study reveals a novel role for IKKα(p45) in DNA repair and cancer therapy.
Keywords:
ATMBRAFDNA-damage RepairIKKcancer treatmentcombination therapyortho-xenograftspatient-derived organoidsphosphorylationtherapy resistance

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