Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• KRAS and NRAS mutations are prevalent in 45% of colorectal cancers.
• Combined MAPK pathway and CDK4/6 inhibition is a potential therapeutic strategy for RAS-mutant colorectal cancer.

Purpose of the Study:

• To evaluate the efficacy and safety of combined MEK and CDK4/6 inhibition in RAS-mutant colorectal cancer using a co-clinical trial approach.
• To identify biomarkers of response and mechanisms of acquired resistance to this combination therapy.

Main Methods:

• Utilized patient-derived xenografts (PDX) for co-clinical evaluation of dual MEK and CDK4/6 inhibition.
• Conducted a clinical safety lead-in trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations.
• Investigated mechanisms of acquired resistance and tested reversal strategies using a SHP2 inhibitor.

Main Results:

• 60% tumor regression observed in 18 PDX models treated with dual MEK and CDK4/6 inhibition, meeting the primary endpoint.
• Prolonged duration of response was predominantly observed in TP53 wild-type models.
• Clinical safety lead-in confirmed safety and showed preliminary activity; feedback activation of receptor tyrosine kinases was identified as a resistance mechanism.

Conclusions:

• Combined MEK and CDK4/6 inhibition demonstrates significant clinical potential for treating RAS-mutant colorectal cancer.
• Patient-derived xenograft models are valuable for co-clinical drug development and understanding resistance mechanisms.
• Targeting SHP2 can overcome acquired resistance to MEK and CDK4/6 inhibitors.