Abstract 1041: Targeted inhibition of c-MET, Axl and DDR signaling pathways by merestinib enhances gemcitabine/nab-paclitaxel standard chemotherapy activity in pancreatic cancer models

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in Western countries. Gemcitabine (Gem) plus nab-paclitaxel (NPT) is the standard chemotherapy treatment for PDAC leading to an average survival of 8.5 months. Activated signaling of c-MET, Axl and DDR1/2 pathways have been implicated in tumorigenic growth in many cancers including PDAC. Merestinib (Mer) is a potent, multikinase inhibitor that blocks c-MET, Axl and DDR1/2 pathways with IC50 values in the low nanomolar range. In this study, we investigated the antitumor potency of merestinib to enhance standard chemotherapy response in preclinical PDAC models. Methods: In vitro cell proliferation assays of PDAC-associated cells were evaluated by colorimetric WST-1 reagent. The mechanism of action was determined by Immunoblot analysis. Tumor growth studies were conducted in 6-week-old female NOD/SCID mice in subcutaneous xenografts. Results: In human PDAC AsPC-1 cell-derived subcutaneous xenografts, gemcitabine plus nab-paclitaxel and merestinib inhibited tumor growth while their combination had an additive effect. The net increase in tumor size was 357 mm3 in controls, 102 mm3 after Gem+NPT, 177 mm3 after Mer and 66 mm3 after Gem+NPT+Mer. Gemcitabine plus nab-paclitaxel and merestinib suppressed in vitro cell proliferation of PDAC epithelial cells and stromal cells. Importantly, the combination treatment demonstrated additive inhibitory effects. Inhibition in cell proliferation by Gem+NPT, Mer and Gem+NPT+Mer treatments was 54%, 14% and 82% (AsPC-1 cells, at medium dose levels), 54%, 4% and 73% (PANC-1 cells, at the highest dose level), 55%, 58% and 92% (PDAC-associated fibroblasts, at the medium dose level). Immunoblot analysis revealed that merestinib caused a decrease in the expression of phospho-c-MET, phospho-Axl, phospho-IGF-1R, phospho-AKT and an increase in apoptosis-related protein cleaved caspase-3 in PDAC cells either alone or in combination with gemcitabine plus nab-paclitaxel. Conclusion: Simultaneous inhibition of c-MET, Axl and DDR1/2 pathways by merestinib has antitumor efficacy in PDAC and it can significantly improve the standard chemotherapy response. This therapeutic approach might lead to a clinically relevant combination to increase PDAC patients' survival. Citation Format: Eda Shi, Margaret A. Schwarz, Md Sazzad Hassan, Urs von Holzen, Roderich E. Schwarz, Niranjan Awasthi. Targeted inhibition of c-MET, Axl and DDR signaling pathways by merestinib enhances gemcitabine/nab-paclitaxel standard chemotherapy activity in pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1041.