Abstract LB-B29: Combined inhibition of MAPK and PI3K signaling augments standard chemotherapy response in preclinical models of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with mortality closely paralleling incidence despite substantial advances in biological understanding of the disease. Nab-paclitaxel (NPT) plus Gemcitabine (Gem) represents the current standard for systemic therapy of advanced PDAC. More than 90% of PDACs harbor an activating mutation in the KRAS oncogene. Presently, no therapeutics exist that effectively target this oncogene, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling pathways. The RAF-MEK-ERK (MAPK) and the AKT-PI3K signaling pathways are well-described mediators of KRAS induced transformation and tumorigenesis in several cancers including PDAC and represent potential targets for combination therapy. We evaluated combination treatment benefits of NPT+Gem with the MEK inhibitor trametinib (Tra) and the AKT inhibitor MK-2206 (MK) in preclinical models to evaluate their therapeutic potential against PDAC. An animal survival study was performed in peritoneal dissemination model in NOD/SCID mice. Tumor growth inhibition studies were performed in subcutaneous PDAC cell-line-derived xenografts and PDAC patient-derived xenografts in mice. Intratumoral mechanism of action was determined by immunohistochemistry (IHC) and Immunoblot analysis. Median animal survival in peritoneal dissemination PDAC xenografts in mice revealed that the median survival was 21 days in controls, which was significantly improved by the NPT+Gem combination (35 days, a 67% increase over controls). Median survival was further increased by addition of trametinib or MK-2206 to the NPT+Gem chemotherapy regimen: NPT+Gem+Tra (43 days, a 105% increase over controls), NPT+Gem+MK (39 days, a 86% increase over controls) and NPT+Gem+MK+Tra (48 days, a 129% increase over controls). In human subcutaneous xenografts using AsPC-1 PDAC cells, trametinib and MK-2206 were also able to enhance NPT+Gem effects. Compared to controls (100±34.8), the percent net local tumor growth in different therapy groups was 21.8±5.9 for NPT+Gem, 7.1±11.2 for NPT+Gem+Tra, 17.2±4.8 for NPT+Gem+MK and 5.7±9.1 for NPT+Gem+MK+Tra. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. Furthermore, in vivo effects of trametinib and MK-2206 correlated with reduced expression of phospho-ERK and phospho-AKT in tumor samples. More importantly, in a recently completed patient-derived xenograft study, we observed that the addition of trametinib or MK-2206 again augmented the NPT+Gem tumor growth inhibition response. In this experiment, compared to controls (350 mm3), the net local tumor growth in different therapy groups was 145.4 mm3 for NPT+Gem, 122 mm3 for NPT+Gem+Tra, 20.4 mm3 for NPT+Gem+MK and -43.7 mm3 (tumor regression) for NPT+Gem+MK+Tra. These findings from multiple preclinical model settings suggest that the effects of NPT+Gem can be enhanced through combined inhibition of MAPK and PI3K signaling, which supports the potential of these targets for clinical PDAC therapy. Citation Format: Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A. Schwarz, Roderich E. Schwarz. Combined inhibition of MAPK and PI3K signaling augments standard chemotherapy response in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B29.