Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

Abstract

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/ mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway

“…E R K phosphorylation activates multiple substrates, which then regulate cell proliferation, apoptosis, metabolism, and immune response (17). The deregulation of the MEK/ERK pathway is common in cancer, such as ovarian cancer, melanoma, and PAAD (17,18). Besides, MEK/ERK inhibitors are proved to increase the radiosensitivity of cancer cells (19).…”

Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review)

“…In the peritoneal dissemination animal survival model, NVP-BEZ235 enhanced gemcitabine response (median survival in days was 16, 21, 28 and 30 in control, NVP-BEZ235, gemcitabine, and combination; P<0.05) (50). In PDAC subcutaneous xenografts, NVP-BEZ235 exhibited synergistic tumor growth inhibition in combination with pan-histone deacetylase inhibitor panobinostat (51) or inRas37 antibody (52). In vitro study using PANC-1 and MIA PaCa-2 PDAC cells revealed that NVP-BEZ235 markedly induced the ERK/MEK pathway.…”