Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. Significance: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.

USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

“…S2B,C ), indicating that AKT pathway activation is regulated by mTOR pathway as a result of positive feedback rather than by USP21. Moreover, neither forced expression of constitutively activated AKT ( Yan et al 2021 ) nor genetic activation of mTORC1 upstream signaling by Tsc2 depletion was able to drive KRAS* bypass; instead, Tsc2 depletion provoked cell death ( Supplemental Fig. S2D–F ).…”

Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities

“…In preclinical studies, 2-DG sensitized cancer cells to multiple types of chemotherapeutic agent [ 41 , 42 , 43 , 44 ], and paclitaxel enhanced the uptake of 2-DG [ 45 ]. 2-DG sensitized pancreatic cancer cells and tumors to inhibition of MEK [ 46 ], the kinase immediately upstream of MAPK3 in the RAS-induced kinase activation cascade. Thus, combining 2-DG with conventional chemotherapies or other agents that induce glycolysis is a reasonable strategy for improving the cancer therapeutics’ efficacies without significantly increasing toxicity [ 47 ].…”

Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment

“…A completed phase I clinical trial evaluated the effect of 2DG alone and in combination with docetaxel on advanced solid tumors ( 87 ). Studies have also shown that low doses of 2-DG inhibition of glucose metabolism combined with a MEK inhibitor induces apoptosis in krasg12d-driven pancreatic ductal adenocarcinoma cells, and experiments also show that this combination treatment inhibited the growth of xenograft pancreatic ductal adenocarcinoma and prolonged total survival ( 103 ).…”