<b>Source data-Reversing</b><b>RAS(ON) Inhibitor </b><b>Daraxonrasib</b><b> Resistance in </b><b>Pancreatic Cancer</b><b> via p16 mRNA Delivery</b>

Emerging RASinhibitors including daraxonrasib exhibit potent therapeutic efficacy against PDAC, yet their efficacy is compromised by acquired resistance. CDKN2A, a pivotal tumor suppressor encoding p16, is frequently inactivated in PDAC.

We identify loss of CDKN2A as a determinant of therapeutic resistance to daraxonrasib.Hence, we report a novel combination strategy for PDAC therapyusing p16 mRNA-loaded lipid nanoparticle (p16-LNP) and daraxonrasib, in which p16-LNP restoresp16 protein to reverse daraxonrasib resistance of PDAC cells characterized by elevated CDK4/6 signaling. This combination markedly induces tumor cell senescence and delaystumor recurrencein multiple PDAC models, including subcutaneous, large-tumor, and orthotopic models.Molecular and bioinformatic analyses reveal that this combined effect is accompanied by suppression of the CDK4/6, MAPK, and PI3K/AKT pathways.These findings highlight the therapeutic potential of p16-LNP for mRNA-based cancer therapy and provide a viable approach to overcome daraxonrasib resistance in PDAC.</p>