Abstract C076: In vitro and in vivo combination of ARQ 751 with PARP inhibitors, CDK4/6 inhibitors, Fulvestrant and Paclitaxel

Background: Dysregulation of the PI3K/AKT signaling pathway is associated with various types of cancers. AKT can be activated through activated receptor tyrosine kinases, gain-of-function mutations of PIK3CA, PTEN deficiency, or AKT amplification or activating mutations such as AKT1-E17K. It has been shown that the PI3K/AKT pathway has contributed to the resistance of conventional chemotherapy, radiation and other targeted therapies. AKT inhibitors have been extensively studied in the clinic and enhance the effects of targeted therapy, chemotherapy and radiation therapy. ARQ 751 is a second-generation AKT inhibitor, which has distinct physico-chemical properties as compared to ArQule’s first-generation inhibitor, miransertib (ARQ 092). ARQ 751 is currently in a phase 1 clinical study in molecularly defined cancer patients. In this study, we assessed the combined effect of ARQ 751 with PARP inhibitors, CDK4/6 inhibitors, an estrogen receptor antagonist and a chemotherapeutic agent both in vitro and in vivo. Methods: In vitro anti-proliferative studies were performed using MTS or Celltiter-Glo as either single agents or in combination with other therapeutic agents. The combination index was calculated based on Cho-Talalay method. In vivo efficacy was tested in patient-derived breast cancer tumors bearing AKT1-E17K mutations and breast cancer cells with PIK3CA mutations. Reverse phase protein arrays (RPPA) were performed on xenograft tumor tissues. Results: ARQ 751 in combination with the PARP inhibitors exhibited enhanced anti-proliferative activity in MDA-MB-468 breast cancer cells. The combination of ARQ 751 and olaparib also suppressed anchorage-independent growth in MDA-MB-231 and HCC1143 cells. In combination with the CDK4/6 inhibitor, ribociclib, ARQ 751 demonstrated superior cell growth inhibition in comparison to the single agents. A synergistic effect was observed at a majority of combination concentration points. In the in vivo efficacy study in a xenograft model with HCC-1954 breast cancer cells, combined treatment of ARQ 751 at 25 mg/kg and paclitaxel at 15 mg/kg showed enhanced antitumor activity with TGI of (90%) in comparison to ARQ 751 alone (46%) or paclitaxel alone (44%) after 3-weeks of treatment. Furthermore, an estrogen receptor positive patient-derived tumor xenograft model harboring the AKT1-E17K mutation was used to assess the effect of ARQ 751 in combination with either fulvestrant or palbociclib or both agents. Combination of ARQ 751 at 25 mg/kg with either fulvestrant at 2.5 mg/kg or palbociclib at 50 mg/kg exerted tumor growth inhibition of 91% or 93%, respectively, as compared to 69% for ARQ 751, 68% for fulvestrant and 38% for palbociclib. When the three agents were combined, tumor regression (TGI >100%) was observed. In order to understand the molecular mechanism involved in the superiority of the combined effect, a RPPA study from xenograft tumor tissues is being performed to assess any alterations in several key pathways. Conclusions: ARQ 751, a highly potent and selective next-generation AKT inhibitor, is combinable with various therapeutic agents including PARP inhibitors, an ER antagonist, CDK4/6 inhibitors, and a chemotherapeutic agent, in vitro and in vivo. The data support the rationale for testing these combinations in the clinic. Citation Format: Yi Yu, Alden Harring, Eva Volckova, Ronald E Savage, Brian Schwartz. In vitro and in vivo combination of ARQ 751 with PARP inhibitors, CDK4/6 inhibitors, Fulvestrant and Paclitaxel [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C076. doi:10.1158/1535-7163.TARG-19-C076