1944P - Pharmacological screening with Chk1 inhibitors identifies synergistic agents to overcome resistance to platinums in basal breast and ovarian cancer

Abstract

BackgroundMetastatic ovarian and basal-like breast cancers are incurable diseases with limited therapeutic options. In our study, we explored synergistic interactions of Chk1 inhibitors (rabusertib and SAR020106) with approved therapies in these indications. In addition, we evaluated the role of these agents to overcome platinum resistance. MethodsWe evaluate the effect of rabusertib and chemotherapic agents in ovarian (OVCAR3, OVCAR8, IGROV1, SKOV3) and breast (MDA-MB-231, HS578T, BT549, HCC3153) cancer cell lines. We also use the commercially available cell line A2780Rcis and a breast cancer model created in our laboratory, MDA-MB231Rcis. ResultsThe combination of platinum agents, cisplatin and carboplatin was synergistic with Chk1 inhibitors rabusertib and SAR020106 in most of basal-like and ovarian cancer cell lines. The combination of rabusertib with gemcitabine was very synergistic in basal-like cell lines but not in ovarian cancer. Doxorubicin, another DNA damaging agent, was also synergistic in ovarian cell lines, but showed less activity in the breast models. Combinations with topotecan were slightly synergistic only in basal-like tumors. The combination of rabusertib with agents that target mitosis were not synergistic. The combination of Chk1 inhibitor with platinum compounds or gemcitabine affects colony formation and tumor invasiveness. Combination of platinum agents and gemcitabine with rabusertib induced cell death that was mainly mediated by caspases. The effect of rabusertib on platinum resistance showed addition of Chk1 inhibitor to cisplatin induces cell death in cisplatin resistant cells. ConclusionsInhibition of Chk1 has a strong synergistic interaction with DNA damaging agents, including platinum compounds, gemcitabine and olaparib, on both tumor types. The effect of rabusertib with platinum agents and gemcitabine on colony growth and long-term effect confirms the effect on proliferation, invasion and long-term survival in basal-like and ovarian cancer cell lines. Addition of rabusertib to cisplatin induces cell death in all the cell lines including the resistant cells, demonstrate that resistance to cisplatin can be overcome by inhibition of Chk1 kinase. Legal entity responsible for the studyAlberto Ocaña. FundingInstituto de Salud Carlos III (PI16/01121) Diputación de Albacete and CIBERONC CRIS Cancer Foundation cancer association ACEPAIN research program of the UCLM regional fellowship for Biomedicine and Health science research (II-2018_11). DisclosureAll authors have declared no conflicts of interest.