fig1
Figure 1. KRAS allelic heterogeneity and representative preclinical resistance mechanisms in PDAC. (A) Distribution of KRAS alterations across solid tumors with a mutation frequency of ≥ 10%. In this aggregated cBioPortal dataset, KRAS alterations were identified in 79.73% of 4,618 patients with PDAC; 77.09% corresponded to gene mutations, while the remaining cases included amplifications and multiple alterations. This value is lower than the > 90% KRAS mutation frequency commonly reported in dedicated PDAC cohorts, likely because aggregated datasets differ in cohort composition, tumor purity, sequencing depth, and definitions of KRAS mutation vs. broader genomic alteration. In colorectal carcinoma, KRAS was altered in 48.98% of 1,225 patients analyzed, with 47.76% representing gene mutations. In lung cancer, KRAS alterations were identified in 30.67% of cases, consistent with previously reported frequencies. The graph was generated using cBioPortal by combining 241 non-redundant studies; (B) Distribution of KRAS-mutant alleles in PDAC. G12D is the predominant KRAS alteration (~40%), followed by G12V (~35%) and G12R (~17%), whereas G12C is less frequent (~2%)[12]. Created in GraphPad Prism (v9.0); (C) Representative resistance mechanisms associated with KRAS G12C-, G12D-, and G12V-mutant PDAC reported in preclinical models. The mechanisms include KRAS copy-number gain, secondary mutations, RTK/MAPK reactivation, PI3K signaling, SRC signaling, EMT/YAP-mediated cellular plasticity, ABCB1-mediated drug efflux, and stromal/TME remodeling. Check marks indicate mechanisms reported in preclinical models carrying the indicated KRAS allele; blank cells indicate that no allele-specific evidence was identified in the reviewed literature [16,38,39,42-46,47,49,52-54,62,66,67,74,75,95,97]. These mechanisms are not necessarily allele-exclusive, and clinical validation remains limited; (D) Conceptual representation of how KRAS allelic heterogeneity may contribute to distinct, partially overlapping resistance programs and potentially divergent responses to KRAS-targeted therapies, highlighting the need for predictive biomarkers, rational combination strategies, and patient stratification. PDAC: Pancreatic ductal adenocarcinoma; RTK: receptor tyrosine kinase; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; SRC: proto-oncogene tyrosine-protein kinase Src; EMT: epithelial-to-mesenchymal transition; YAP: Yes-associated protein; ABCB1: ATP-binding cassette subfamily B member 1; TME: tumor microenvironment.
