Abstract B096: Mutant and Wildtype RAS Crosstalk and Stoichiometric Deficiencies Determine Sensitivity to RAS Pathway Targeted Therapies

Therapies targeting the RAF-MEK-ERK pathway are generally considered to have limited efficacy in KRAS mutant cancers when compared to the FDA approved RAS inhibitors such as sotorasib and adagrasib. However, specific KRAS mutations, exhibit distinct behaviors. Notably, KRAS G12R pancreatic ductal adenocarcinoma (PDAC) tumors, in the preclinical setting and rare case reports, have shown sensitivity to MEK inhibitors (MEKi) with autophagy inhibitors, though the underlying mechanisms remain poorly understood. Using a systems-level approach, we uncovered a mechanistic explanation for this phenomenon. Due to distinct biophysical properties, KRASG12R has an impaired ability to activate wild-type RAS (WT-RAS) compared to other KRAS mutations, such as KRASG12D. This reduced activation stems from the weaker interaction between KRASG12R and guanine exchange factors (SOS), as well as the tumor suppressor neurofibromin (NF1), crucial in regulating WT-RAS activity. The impaired ability to activate WT-RAS leads to a weaker holistic MAPK signaling in KRASG12R driven tumors, which leads to the increased sensitivity to MEKi. To confirm our preclinical findings, we further analyzed the utility of MEKi with hydroxychloroquine, an autophagy inhibitor, in patients with KRAS G12R mutated metastatic PDAC. Five of the eight patients (62.5%) treated in first- or second-line settings had a progression-free survival exceeding 6 months. Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size which lasted for 8.9 months. Furthermore, we had a patient harboring a KRAS G12R mutation who achieved disease control on Divarasib (RMC-6236) but subsequently became resistant. We identified that the patient's tumor RAS stoichiometry shifted from RAS-mut^high/WT-low to RASmut-low/RASWT-high ratios. We found that the inhibitory effects of Daraxonrasib on wild-type RAS were insufficient to halt tumor growth. However, we were able to achieve progression-free survival by utilizing MEK inhibitor plus hydroxychloroquine (MEKi+HCQ). Overall, our work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies. Citation Format: Thomas McFall, Mandana Kamgar. Mutant and Wildtype RAS Crosstalk and Stoichiometric Deficiencies Determine Sensitivity to RAS Pathway Targeted Therapies [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): nr B096.