Abstract 3508: Combination of the Chk1 inhibitor (prexasertib) with a PI3K/mTOR inhibitor (LY3023414) induces synergistic anti-tumor activity in triple negative breast cancer (TNBC) models

Abstract

Abstract TNBC, the most aggressive subtype of breast cancer, is characterized by high level of genomic instability, defects in DNA damage response (DDR) and increased replication stress (RS). The current treatment options for TNBC are limited and new approaches are needed. Checkpoint kinase 1 (Chk1) is a key protein kinase that regulates the cell cycle, DNA damage and RS response, and has emerged as an attractive target for anticancer therapy. Prexasertib, an ATP-competitive inhibitor of Chk1 has demonstrated activity in vitro and in vivo across a variety of tumor histologies. Prexasertib is being evaluated in patients with TNBC in a Phase II study sponsored by NCI (NCT02203513). The preliminary results reported in 2016 showed modest single agent activity. PI3K/AKT/mTOR is a critical pathway with key roles on cancer cell survival, homologous recombination repair and drug resistance. Our previous study indicated the expression level of genes related to PI3K/AKT signaling is elevated in prexasertib resistant TNBC patient-derived xenograft (PDX) models. It is hypothesized that inhibiting both the Chk1 and PI3K/AKT pathway may improve prexasertib efficacy. In this study, we evaluated the combination effect of prexasertib with a PI3K/mTOR inhibitor (LY3023414, a selective dual inhibitor of PI3K and mTOR, which is being investigated in Phase 2 clinical trials) in TNBC in vitro and in vivo. The prexasertib/LY3023414 combination induced the synergistic or additive inhibition on cell proliferation in 10 of 12 TNBC cell lines. The prexasertib/LY3023414 combination enhanced DNA damage (γH2AX), replication stress (phospho-RPA32) and proliferation inhibition in MDA-MB-231 cells when compare with single agent treatment. In three TNBC xenograft models (HCC1806, HCC1187 and MX-1) LY3023414 induced 0%, 62% and 24% tumor inhibition; prexasertib induced 94%, 78% and 96% tumor inhibition; and the combination led to 35%, 61% and 21% tumor regression, respectively. The prexasertib/LY3023414 combination also increased the inhibition of both primary tumor growth and spontaneous lung metastasis in a MDA-MB-231 mammary fat pad orthotopic model when compared with the respective single agent activity. The efficacy of prexasertib/LY3023414 combination was further assessed in 38 TNBC PDX models, and the combination showed a synergistic effect in 8 of 38 models and an additive effect in 22 of 38 models. Overall, the combined inhibition of Chk1 and PI3K/mTOR pathway enhanced antitumor activity in TNBC models. Taken together, these data will inform the clinical development of potential combination of Chk1 inhibitor prexasertib with a PI3K/mTOR inhibitor in the treatment of TNBC patients. The safety of this combination is being assessed in an ongoing Phase 1b clinical trial (NCT02124148), which includes an expansion cohort focused on patients with TNBC. Citation Format: Wenjuan Wu, Greg Donoho, Philip Iversen, Jack Dempsey, Andrew Capen, Mark Castanares, Jennifer Stephens, Karsten Boehnke, Christoph Reinhard Reinhard, Aimee Lin. Combination of the Chk1 inhibitor (prexasertib) with a PI3K/mTOR inhibitor (LY3023414) induces synergistic anti-tumor activity in triple negative breast cancer (TNBC) models [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 3508.