Simultaneous Targeting of KRAS and CDK4 Synergistically Suppresses Pancreatic Cancer Cells

Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule inhibitors of KRAS have been developed, bearing high potential for cancer therapy but considerable risk of resistance development. To avoid cancer cell adaptation, effective combinatorial partners for increasing immediate efficacy remain to be explored. Here, we demonstrate that combining the KRAS inhibitor Sotorasib with the CDK4/6 inhibitor Palbociclib synergistically eliminates pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS G12C mutations. This synergy was particularly pronounced after drug washout, indicating a durable impact. Similar effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, MRTX1133, a KRAS G12D inhibitor, synergized with Palbociclib to suppress KRAS G12D-mutant PDAC-derived cells. Mechanistically, these combinations induced sustained cell cycle arrest through reduced RB phosphorylation, decreased E2F1 levels, and increased CDKN1B/p27 expression. Deletion of CDKN1B largely rescued tumor cell proliferation, underscoring its critical role in mediating the observed synergy. These findings support the therapeutic potential of combining KRAS and CDK4/6 inhibitors for treating PDAC and other Ras-driven cancers.