Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Title: Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers PI: Kirsten L. Bryant, PhD Description/Abstract Autophagy is a self-degradation process whereby cells can orderly clear defective organelles and recycle macromolecules as a nutrient source. Autophagy is elevated and essential for the tumorigenic growth of KRAS- mutant pancreatic ductal adenocarcinoma (PDAC), providing the rationale for clinical evaluation of the autophagy inhibitor hydroxychloroquine (HCQ) for PDAC. Disappointingly, when used as monotherapy or in combination with standard of care, HCQ has shown limited to no clinical efficacy for PDAC. We recently determined that the treatment of PDAC with inhibitors of the key KRAS effector pathway, the RAF-MEK-ERK mitogenic activated protein kinase (MAPK) cascade, unexpectedly caused further elevation of autophagy, rendering PDAC acutely dependent on this process, and hypersensitive to autophagy inhibition. We determined that ERK inhibition impaired other critical processes that then led to compensatory upregulation of autophagy. Our findings, together with essentially identical conclusions by another independent co-published study, have led to the initiation of clinical trials evaluating either MEK (trametinib, binimetinib) or ERK (LY3214996) inhibitor in combination with HCQ for metastatic KRAS-mutant PDAC. While early observations from compassionate use of this combination support a significant clinical impact, our preliminary studies support our premise that we can improve upon this therapy. We propose two aims to further advance autophagy inhibition as an anti-RAS therapeutic approach. HCQ is a lysosome inhibitor and consequently not selective for autophagy. We hypothesize that inhibitors of the proteins upstream in the autophagy pathway, will synergize with HCQ and more potently and durably inhibit the autophagy pathway. Additionally, a comprehensive evaluation of the effect of inhibition of each individual node of the autophagy pathway on flux in the context of an autophagy-addicted cancer such as PDAC has not been performed. Thus, we will determine the effect of individual and combined inhibition of different nodes of the autophagic pathway on autophagic flux (Aim 1). Our Aim 2 studies are based on our recent observation that PDAC cells upregulate macropinocytosis in response to sustained inhibition of the RAS ERK MAPK pathway. We hypothesize that the upregulation of macropinocytosis facilitates resistance to both RAS- and autophagy- targeted therapeutics. We will characterize the mechanistic signaling underlying macropinocytic upregulation as well as evaluate RAS inhibitor resistant cells to determine whether upregulated macropinocytic activity is a driver of resistance. In summary, our studies will enhance our understanding of regulation of nutrient scavenging pathways in PDAC and aid in the development of novel combination therapies to target autophagy and macropinocytosis for the treatment of KRAS-mutant cancers.