Abstract
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.
Highlights
The treatment of solid tumors is still based mainly on chemotherapy [1]
We selected agents with different mechanisms of action, including those that inhibit the formation of the mitotic spindle, like vinorelbine, docetaxel, or eribulin, and DNA-damaging agents, such as doxorubicin, platinum compounds, gemcitabine, or topotecan
A PARP inhibitor that has recently been approved for the treatment of breast cancers with germ line mutations of the BRCA gene [19]
Summary
The treatment of solid tumors is still based mainly on chemotherapy [1]. the recent identification of molecular alterations in tumors has permitted the design and development of therapies against specific oncogenes [1,2]. Basal-like breast cancer, which includes the triple negative breast cancer subtype (TNBC), is considered an unsolved medical challenge as patient outcome in the advanced stages is short, even after receiving appropriate treatment [10] These tumors are characterized by a high grade of genetic instability and a notable impairment of DNA repair processes [1,11] In this context, DNA-damaging agents like platinum compounds have been positioned as key therapies for the treatment of basal-like tumors. Inactivation of CHK1 permits cell cycle progression without a proper DNA repair, increasing genetic instability and aneuploidy, which may lead to cell death [14,15] For this reason, these DDR inhibitors are promising candidates in the treatment of solid tumors. We evaluated the potential of these compounds to overcome resistance to platinum agents
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