Single-cell RNAseq of from murine pancreas tumor (FPC)

We deployed two complementary preclinical PDAC models, including a degron-regulated KRASG12D-dependent transplantation model, and a KrasG12V-driven PDAC mouse model treated with the RAS(ON) multi-selective inhibitor, RMC-7977, to describe therapeutic response and resistance mechanisms. KRASG12D degradation provoked RAS-dependent relapse, characterized by compensatory wild-type (WT) RAS upregulation, restored MAPK signaling and proliferation, and a shift towards hybrid cancer cell states.

RMC-7977 treatment triggered rapid RAS-independent resistance within 7 days, distinguished by suppressed MAPK yet restored proliferation with increased epithelial differentiation, and upregulation of Fyn. Antagonists of WT RAS or FYN attenuated resistance; and combining FYN antagonism with RMC-7977 prevented the uncoupling of MAPK signaling from cell proliferation in the respective KrasG12V PDAC model. Our findings identify distinct adaptive pathways orchestrating RAS-dependent versus RAS-independent resistance in PDAC and propose combination strategies for clinical evaluation to enhance KRAS-directed therapy durability.