4.7 Article

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

Journal

Publisher

MDPI
DOI: 10.3390/ijms21239034

Keywords

breast cancer; standard-of-care chemotherapies; chemotherapy resistance; DNA damage response (DDR); CHK1 inhibitors; DNA-damaging agents; platinum compounds; synthetic lethality

Funding

  1. Instituto de Salud Carlos III [PI16/01121, PI19/00808]
  2. Diputacion de Albacete
  3. CIBERONC
  4. CRIS Cancer Foundation
  5. Junta de Comunidades de Castilla-La Mancha [SBPLY/19/180501/000173]
  6. Cancer Association, ACEPAIN
  7. Implementation Research Program of the UCLM (UCLM)
  8. European Commission/FSE
  9. Junta de Comunidades de Castilla-La Mancha
  10. Regional Centre for Biomedical Research of the UCLM (CRIB-UCLM)
  11. Biomedicine and Health Science Research [II-2018_11]

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Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.

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