Abstract 1608: Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer
Authors: Eva M. Galan-Moya, Ana Alcaraz-Sanabria, Cristina Nieto-Jimenez, Veronica Corrales-Sanchez, Miriam Nuncia-Cantarero, Juan C. Montero, Atanasio Pandiella, Alberto Ocaña
Journal: Cancer Research (2018)

Abstract Basal-like breast cancer and ovarian cancer are considered as unmet entities as patient outcome in advanced stages is short, even receiving the most appropriate treatment. These tumors are characterized by a high grade of genetic instability and a notable impairment of DNA repair processes. Thus, in response to DNA damage, they depend on checkpoint arrest proteins, such as Chek1, to stop division. Inactivation of Chk1 permits cell cycle progression without a proper DNA repair, therefore increasing genetic instability and aneuploidy and eventually leading to cell death. Chk1 inhibitors are currently in clinical development and, therefore, the identification of chemotherapies that could be used as clinical partners to potentiate their effect is a main goal. OVCAR3 and IGROV ovarian cancer cells as well as the basal-like MDA-MB-231 and HS578T cell lines were used to screen for agents that may increase the antiproliferative properties of Chk1 inhibitors. Combination of DNA-damaging agents, like platinum compounds or gemcitabine, with the Chk1 inhibitors LY2603618 and SAR020106 had a synergistic effect, not observed when combined with agents targeting mitosis, like taxotere, eribulin or vinorelbine. A similar antiproliferative effect was observed for PARP inhibitors such as olaparib, reinforcing the concept that inhibition of Chk1 allows cells to enter apoptosis when a relevant genetic instability is present. Clonogenic assays and 3D colony formation studies confirmed the effect observed on proliferation also on invasion and long-term survival. Analyses of cell cycle, cell death and intracellular mediators were performed by flow cytometry and Western blot. The effect of the association of LY2603618 with cisplatin and gemcitabine did not change the cell cycle. However, combination of both agents produced a marked induction of apoptosis. Experiments evaluating caspase activity demonstrated that the principal mechanism associated with the induction of apoptosis was caspase dependent. We also explored combination of agents that have a clear translation to the clinics including double combinations with chemotherapies like cisplatin and gemcitabine. We observed that these triple combinations were more effective than double or single agents. Finally, we wanted to evaluate the antiproliferative effect when adding LY2603618 to olaparib in addition to a DNA-damaging agent. Of note, we observed a higher effect than single-agent olaparib or the chemotherapy. Interestingly, inhibition of Chk1 also reverted the effect of cisplatin in platinum-resistant cells. Our findings support the clinical development of Chk1 inhibitors in combination with DNA-damaging agents in basal-like and ovarian cancer. Citation Format: Eva M. Galan-Moya, Ana Alcaraz-Sanabria, Cristina Nieto-Jimenez, Veronica Corrales-Sanchez, Miriam Nuncia-Cantarero, Juan C. Montero, Atanasio Pandiella, Alberto Ocaña. Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1608.