Inhibition of PI3K/AKT/mTOR signaling by a dual PI3K/mTOR inhibitor (LY3023414) potentiates the antitumor efficacy of the Chk1 inhibitor prexasertib (LY2606368) in models of human high-grade serous ovarian cancer (HGSOC)

HGSOC (characterized by defects in DNA damage repair and high levels of genomic instability and DNA replication stress) is the most lethal gynecological malignancy in the United States. The current treatment options for HGSOC are limited and new approaches are needed. Checkpoint kinase 1 (Chk1), a key protein kinase that regulates the cell cycle, DNA damage and replication stress response, has emerged as an attractive target for anti-cancer therapy. Prexasertib, an ATP-competitive inhibitor of Chk1, is being evaluated in a Phase 2 trial sponsored by NCI (NCT02203513); and the preliminary data showed encouraging results in patients with wild-type BRCA HGSOC. PI3K/AKT/mTOR pathway plays key roles in cancer cell survival, homologous recombination repair and drug resistance. Our previous data showed the expression level of genes related to PI3K/AKT signaling is elevated in prexasertib-resistant TNBC patient-derived xenograft (PDX) tumors. In this study we explored whether the PI3K/AKT/mTOR pathway is involved in prexasertib response of HGSOC and evaluated the combination effect of prexasertib with a PI3K/mTOR inhibitor (LY3023414) on HGSOC in vitro and in vivo. Data from 24 n=1 HGSOC PDX tumors indicated that the tumors with high phospho-AKT were resistant to prexasertib. The PI3K/AKT/mTOR signaling (including p70S6K and S6RP) was activated and correlated with the increased DNA damage (γH2AX) in HGSOC cell lines treated with prexasertib. These data suggest that the PI3K/AKT signaling is associated with prexasertib resistance and the cell survival response to DNA damage induced by prexasertib; and provide the scientific rational for a prexasertib/LY3023414 combination. Indeed the prexasertib/LY3023414 combination induced synergistic or additive inhibition on cell proliferation and colony formation in multiple HGSOC cell lines. This combination enhanced replication stress (phospho-RPA32), DNA damage (γH2AX), S phase arrest and cell death (cleaved PARP and sub-G1) in HGSOC Ovcar-8 cells when compared with single agent activity. Combination efficacy was further tested in HGSOC OV-90 and Cov504 xenograft models. Prexasertib induced tumor inhibition by 58.8% in OV-90 and tumor regression by 37.3% in Cov504, and LY3023414 induced tumor inhibition by 43.37% and 66% in OV-90 and Cov504 tumors, respectively. Prexasertib/LY3023414 combination resulted in tumor regression by 8.9% and 73.7% in OV-90 and Cov504 tumors, respectively, and significantly (p Citation Format: Jack Dempsey, Greg Donoho, Philip Iversen, Jennifer Stephens, Ann McNulty, Ricardo Martinez, Christoph Reinhard, Louis Stancato, Aimee Lin, Wenjuan Wu. Inhibition of PI3K/AKT/mTOR signaling by a dual PI3K/mTOR inhibitor (LY3023414) potentiates the antitumor efficacy of the Chk1 inhibitor prexasertib (LY2606368) in models of human high-grade serous ovarian cancer (HGSOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1761.