Mutant and Wild-Type RAS Cross-talk and Stoichiometric Deficiencies Are Determinants of Sensitivity to Targeted Therapies in KRASG12R Pancreatic Ductal Adenocarcinoma

Therapies targeting the RAF-MEK-ERK pathway are generally considered to have limited efficacy in KRAS-mutant cancers. However, specific KRAS mutants exhibit distinct behaviors. Notably, KRASG12R pancreatic ductal adenocarcinoma (PDAC) tumors have shown sensitivity to MEK inhibitors (MEKi) in combination with autophagy inhibitors, but a better understanding of the underlying mechanisms is needed to optimize this treatment strategy. Using a systems-level approach, we uncovered a mechanistic explanation for this phenomenon. Due to distinct biophysical properties, KRASG12R had an impaired ability to activate wild-type HRAS and NRAS (WT-RAS) compared with other KRAS mutants, such as KRASG12D. This reduced activation stemmed 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 led to weaker holistic MAPK signaling in KRASG12R-driven tumors, which conferred increased sensitivity to MEKi. To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R-mutated metastatic PDAC. Five of the eight (62.5%) patients 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 that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of patients with PDAC most likely to benefit from tailored therapeutic strategies. Significance: The unique sensitivity of KRASG12R-mutant cancers to MEK inhibitors offers a critical advancement in understanding MAPK signaling and paving the way for precision-targeted therapies in previously untreatable contexts. See related commentary by Tiriac and Engle, p. 1817 See related article by Burge et al., p. 1854 See related article by Burge et al., p. 1868.