Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Clark, Geoffrey

Committee Member

Donninger, Howard

Committee Member

Beverly, Levi

Committee Member

Mitchelle, Robert A.

Committee Member

Ceresa, Brian

Author's Keywords

RAS; RALGEF; cancer; drug

Abstract

The RALGEF family of proteins are direct downstream effectors of the RAS oncoprotein. RALGEFs act as guanine nucleotide exchange factors (GEFs) for downstream RAL proteins, thus tying RAS to the regulation of RAL. Genetic studies have demonstrated RAL proteins to be key drivers of RAS-driven transformation and metastasis. Furthermore, this pathway has been implicated in chemoresistance, exocyst-mediated transport, and the modulation of cancer stem cells. Previous work in our lab reported the activity of a novel pan-RALGEF inhibitor (C4-180) against RAS-driven pancreatic cancer models. Here we show the agent to be active against in vitro and in vivo models of KRAS-driven non-small cell lung cancer (NSCLC). Treatment with the agent is also able to suppress RALBP1 function in chemoresistance, modulate exocyst dynamics, and demonstrate activity against the cancer stem cell subpopulation. Overall, we identify a possible therapeutic approach to the treatment of mutant-RAS NSCLC.

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