Transcriptional and Epigenetic Plasticity Drive an Alternative Non-clonal Mechanism of Resistance to Kras G12D Inhibition in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by an aggressive clinical course and profound resistance to systemic therapies [1]. Oncogenic mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in more than 90% of PDAC cases, with KRASG12D representing the most frequent and clinically relevant allele [2]. The recent development of allele-specific noncovalent inhibitors targeting KRASG12D represents a major breakthrough. Among these, MRTX1133 selectively binds KRASG12D, locking it in its inactive guanosine diphosphate-bound state, and has shown strong antitumor activity in preclinical models, raising expectations for clinical translation [3]. However, emerging evidence indicates that therapeutic responses are limited by the rapid onset of resistance, whose mechanisms remain poorly understood [4]. While resistance is traditionally linked to clonal genetic evolution, including secondary mutations in drug target, bypass signaling pathways’ activation, or copy-number-driven oncogene amplification [5], these mechanisms do not fully explain the rapid and extensive resistance observed in PDAC. This suggests a role for additional nongenetic processes. Notably, PDAC exhibits high plasticity, with extensive transcriptional and phenotypic reprogramming [6]. We therefore hypothesized that resistance to KRASG12D inhibition may partly arise from adaptive, non-clonal mechanisms driven by transcriptional and epigenetic changes.