Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Experimental Pathology

First Advisor

Muzumdar, Mandar

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive human malignancies, with a five-year survival rate of less than 13%. Oncogenic KRAS mutations occur in over 90% of cases and drive tumor initiation and progression, making KRAS a desirable therapeutic target. Despite the development of direct KRAS inhibitors, clinical efficacy has been modest due to rapid adaptive resistance. This thesis primarily investigates the molecular mechanisms by which PDAC cells adapt to KRAS inhibition, while also uncovering co-vulnerabilities that can be therapeutically exploited. Chapter 1 provides a comprehensive literature review of KRAS biology in PDAC, summarizing historical and contemporary findings on KRAS-driven signaling, mechanisms of resistance, and emerging therapeutic targeting strategies. This review establishes the conceptual foundation for the experimental studies presented in subsequent chapters. In Chapter 2, I demonstrate that PI3K regulates wild-type RAS signaling through remodeling of the RAS signalosome, thereby sustaining MAPK pathway activity when mutant KRAS is absent or pharmacologically inhibited. This rewiring defines PI3K as an upstream bypass regulator that limits KRAS inhibitor efficacy and creates a rationale for dual PI3K/KRAS blockade. In Chapter 3, I use genome-wide CRISPR/Cas9 screening to identify particular genetic dependencies in KRAS-deficient PDAC cells. Among these, KSR1 emerged as an actionable co-vulnerability, expanding the therapeutic landscape beyond direct KRAS inhibition. Moreover, I identified reversible adaptive resistance mechanism in MIA PaCa-2 through EGFR reactivation implying combination strategy with EGFR inhibitor. Finally, I contributed as the second author to two additional studies. Chapter 4 provides mechanistic insight into how oncogenic KRAS mutations affect KRAS oligomerization status, defining how the RAS membrane nanoenvironment is important for signaling transduction. Chapter 5 explores a role for KRAS in facilitating uptake of dietary unsaturated fatty acids to mold the pancreatic phospholipid landscape to dictate tumor fate. Together, this thesis reveals the multi-dimensional functions of KRAS signaling, dissects resistance mechanisms to KRAS inhibition, and nominates promising candidates for developing more effective therapies.

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