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

作者：Mandana Kamgar, G. Aaron Hobbs, Raven Davidson, Daniel Dorbin, Juliannie Herrera, John Fairbanks Langenheim, Rachel A. Burge, Mohammed Aldakkak, Ryan D. Conrardy, Anikó Szabó, Sam Z. Thalji, Bradley Mayer, Justin J. Grahl, Brian Y. Chung, Alexandria T. Phan, James P. Thomas, Yongwoo David Seo, Douglas B. Evans, Kathleen K. Christians, Beth E. Erickson, William Adrian Hall, Ben George, Susan Tsai, Nikki K. Lytle, Channing J. Der, Razelle Kurzrock, Thomas B. McFall · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-25-0018 · 被引用次数：4 · 研究领域：Autophagy in Disease and Therapy、Pancreatic and Hepatic Oncology Research、Melanoma and MAPK Pathways

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...