Targeting Distinct Cell Cycle Nodes Overcomes RAS Inhibitor Resistance.

Targeting cell cycle regulators CDK4/6 and CDK2 overcomes resistance to KRAS inhibitors in pancreatic and lung cancers, achieving durable tumor control.

• Why it matters: Resistance to KRAS-targeted therapies limits their long-term effectiveness, as resistant cancer cells maintain cell cycle progression despite suppressed KRAS signaling.
• What they did: Researchers used transcriptomic, proteomic, drug screening, and CRISPR-Cas9 approaches to identify that disrupting cell cycle nodes with CDK4/6 or CDK2 inhibitors restores sensitivity and delays resistance.
• The result: Co-inhibition of KRAS with CDK4/6 or CDK2 induced sustained tumor suppression in vivo, highlighting cell cycle activity as a key resistance feature and supporting combined targeting as a promising therapeutic strategy.