Molecular and Medical Pharmacology
University of California, Los Angeles (UCLA)
Los Angeles, CA
Mapping and Targeting Nucleotide Biosynthetic Plasticity in Mutant KRAS Driven Pancreatic Cancer
Aim: Basic Science / Cancer Biology
Pancreatic cancer, or pancreatic ductal adenocarcinoma (PDAC), is a highly recalcitrant malignancy for which effective therapies are urgently needed. This proposal aims to determine how mutant KRAS, the major oncogenic driver of pancreatic cancer, controls the ability of cancer cells to produce and utilize nucleotides essential for tumor growth and survival. Mutant KRAS orchestrates major metabolic adaptations critical for pancreatic cancer progression. However, how mutant KRAS impacts nucleotide metabolism has received far less attention despite the fact nucleotides play critical roles in cell division and protein expression. In particular, there are significant gaps in knowledge as to how mutant KRAS regulates the production and utilization of a class of nucleotide, pyrimidines, and how this regulation impacts the metabolism of mutant KRAS cells. Knowledge gained from these studies will be used to identify novel targetable tumor-specific metabolic vulnerabilities in PDAC and, potentially, other mutant KRAS-driven malignancies.