Abstract 4034: Inhibition of AXL improves response to platinum and taxane in chemotherapy-resistant uterine and ovarian cancers

Abstract

Abstract AXL expression has been associated with decreased survival in uterine serous cancer (USC) and high-grade ovarian serous cancer (HGSOC). We determined whether therapeutic inhibition of AXL with BGB324, which is in Phase I/II clinical trials for solid tumors, would improve chemotherapy response in chemotherapy resistant uterine and ovarian cancers. Taxane and platinum resistant ovarian and uterine cancer cell lines were used for in vitro cell viability (XTT) assays. Selective small molecule inhibition of AXL was achieved using BGB324. Western blotting was used to detect protein expression and activation. Tritium-labeled paclitaxel was utilized to measure chemotherapy accumulation in cancer cells. In vivo subcutaneous models were performed with the USC cell line ARK1 and patient-derived HGSOC xenografts (PDX). Statistical significance (p<0.05) and IC50 determination was assessed using Prism7. Upon AXL inhibition by BGB324, the HGSOC cell lines OVCAR5, OVCAR3TP, and OVCAR3TPMes demonstrated a dose-dependent sensitization to paclitaxel and carboplatin chemotherapy. BGB324 treatment of OVCAR3TPMes cells improved response to carboplatin from untreated (IC50 of 73uM) to IC50 of 66uM, 51uM and 31uM at 0.25uM, 0.5uM, and 1uM, respectively (p<0.01). Similarly, paclitaxel response improved from untreated (IC50 of 15.4nM) to IC50 of 13.0nM, 11.3nM and 9.8nM at 0.25uM, 0.5uM, and 1uM, respectively (p<0.05). To assess the dynamics of this chemoresponse, ARK1 USC cells were pre-treated with 0.5uM BGB324 and 1.0uM BGB324 and demonstrated a 31% and 43% increase in intracellular 3H-paclitaxel accumulation, respectively, when compared to cells without AXL inhibition (p<0.05). RT-PCR was utilized to detect changes in multidrug resistance protein transcripts; mRNA levels of P-Glycoprotein (PGP) had a 6.3-fold reduction in OVCAR3TPMES cells treated with 1uM BGB324 (p<0.05). This suggests that inhibition of AXL contributes to chemoresistance by increasing exposure of paclitaxel in tumor cells. The combination of paclitaxel and BGB324 therapy decreased USC tumor volume by 51-67% when compared to treatment with paclitaxel, BGB324, or vehicle control alone (p<0.05). In PDX models, BGB324 therapy improved tumor response with combined carboplatin and paclitaxel therapy when compared to chemotherapy alone, inhibitor alone, or vehicle control (77%, 87%, and 88% decrease in tumor volume at day 11, respectively, p<0.0001). AXL expression contributes to platinum and taxane chemoresistance, and therapeutic inhibition of AXL with BGB324 restores chemosensitivity in ovarian and uterine cancer cell lines and patient derived xenograft models. Based on this data, chemoresistant tumors with AXL expression could be considered for treatment with BGB324 to restore chemosensitivity to carboplatin and paclitaxel. Citation Format: Jeanne Quinn, Marguerite Palisoul, Lei Guo, Andrea Hagemann, Matthew Powell, David Mutch, Carolyn McCourt, Premal Thaker, Katherine Fuh. Inhibition of AXL improves response to platinum and taxane in chemotherapy-resistant uterine and ovarian cancers [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 4034.