Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Activating KRAS mutations are key drivers in pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC).
• Current KRAS inhibitors offer clinical benefits but face resistance, limiting durable responses.
• Resistance mechanisms involve sustained cell cycle progression despite suppressed KRAS signaling.

Purpose of the Study:

• To investigate the mechanisms of resistance to KRAS/RAS inhibitors in PDAC and NSCLC.
• To identify therapeutic strategies to overcome acquired resistance to KRAS-directed therapies.
• To evaluate the efficacy of co-targeting cell cycle kinases with KRAS/RAS inhibitors.

Main Methods:

• Transcriptomic and proteomic analyses to understand resistance mechanisms.
• Combinatorial drug screening and genome-wide CRISPR-Cas9 screening.
• In vivo studies using xenograft models of acquired resistance.

Main Results:

• Resistant cells sustain cell cycle progression, bypassing KRAS inhibition.
• Targeting CDK4/6 or CDK2 restores sensitivity to KRAS/RAS inhibitors.
• Co-targeting CDK2 demonstrated a broader effect and more durable cytostatic response.
• Concurrent inhibition of KRAS with CDK4/6 or CDK2 achieved durable tumor control in vivo.

Conclusions:

• Sustained cell cycle activity is a critical feature of resistance to KRAS-directed therapies.
• Co-targeting cell cycle nodes, particularly CDK2, is an effective strategy to overcome KRAS/RAS inhibitor resistance.
• This approach holds potential for improving durable responses in PDAC and NSCLC patients.