Abstract B020: Oncogenic KRAS drives nutrient transport to support growth in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dense desmoplastic stroma and a nutrient-deprived tumor microenvironment (TME). These harsh conditions drive metabolic symbiosis, where cancer cells, stromal cells, and immune cells exchange metabolites to sustain tumor growth, therapy resistance, and immune evasion. Although MRTX1133 (KRASG12D inhibitor) has demonstrated promise in targeting the KRAS/MAPK pathway, responses differ throughout PDAC subtypes, and resistance has been reported. We treated PDAC cell lines with KRASG12D inhibitor (KRASi) and found a paradoxical increase in proliferation in some cell lines while suppressing growth in others, indicating the activation of compensatory survival mechanisms. In the sensitive cell lines, we found that KRASi disrupted growth, altered the metabolomic profile, and nutrient transport. We have identified SLC20A1, a phosphate transporter, as a novel KRAS-driven transporter. CRISPR/Cas9-mediated knockout of SLC20A1 disrupted the Warburg effect in PDAC cells. In conclusion, our data suggests that KRAS/MAPK inhibition exert robust control on nutrient transport as a mechanism to impair metabolism in KRAS-reliant PDAC cells. Citation Format: Harshita Nivrutti. Khedkar, Laiba Naz. Shiekh, Matthew Cheung, Don-Gerard Conde, Zeribe C. Nwosu. Oncogenic KRAS drives nutrient transport to support growth in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B020.