Abstract C077: Elucidation and exploitation of critical nutrient scavenging regulation in ERK MAPK inhibited pancreatic cancer

Abstract

Abstract Alteration of essential metabolic pathways is a major mechanism by which oncogenic KRAS promotes tumor development and growth in pancreatic ductal adenocarcinoma (PDAC). KRAS-driven PDAC is dependent on nutrient scavenging pathways, including macropinocytosis and autophagy to fuel the high metabolic demand of rapid proliferation. Thus, these metabolic processes are attractive targets for the development of treatments for PDAC. KRAS loss results in downregulation of macropinocytosis in PDAC. Additionally, our lab demonstrated that KRAS loss or inhibition of ERK MAPK signaling decreased glucose consumption and glycolysis but increased autophagy, thereby enhancing dependency on autophagy for survival and growth. Accordingly, dual ERK MAPK and autophagy inhibition (via chloroquine) synergistically enhanced anti-tumor efficacy in PDAC. Early clinical data has demonstrated that resistance to this treatment arises over time through unknown mechanisms. Our preliminary data indicates that following ERK MAPK inhibition both autophagy induction and macropinocytosis downregulation is transient—with autophagic and macropinocytic activity returning to/surpassing basal levels after prolonged treatment. The underlying mechanistic and signaling crosstalk between autophagy and macropinocytosis remains poorly understood. We hypothesize that there is compensatory regulation between autophagy and macropinocytosis signaling following ERK MAPK inhibition. We propose that prolonged activation of autophagy upregulates macropinocytosis over time, consequently abrogating dependency on autophagy and therefore reducing sensitivity to autophagy inhibition. We demonstrate an inverse temporal relationship between autophagic flux and macropinocytosis following genetic loss of KRAS or pharmacological inhibition of the KRAS-ERK MAPK pathway. Furthermore, we show that chloroquine, which is commonly thought of as a lysosomotropic drug, does not prevent degradation of proteins engulfed via macropinocytosis. Together our data suggest that upregulation of macropinocytosis may mediate resistance to the combination of ERK MAPK inhibition and chloroquine. Additionally, we present the unexpected observation that prolonged pharmacological inhibition of the ERK MAPK pathway results in the upregulation of macropinocytosis. Furthermore, we demonstrate that this upregulation of macropinocytosis is accompanied by increased albumin uptake and sensitivity to albumin-bound paclitaxel (nab-paclitaxel). Given the dependence of PDAC on macropinocytic uptake for tumorigenic growth, as well as the potential to exploit macropinocytosis for drug-delivery, it is imperative to understand how ERK MAPK inhibitors regulate macropinocytosis. A better understanding of the regulation underlying these essential metabolic pathways will better inform future ERK MAPK inhibitor combinations. Citation Format: Ryan Robb, Kirsten L. Bryant. Elucidation and exploitation of critical nutrient scavenging regulation in ERK MAPK inhibited pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C077.