Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) exhibits significant genetic diversity among patients.
• RAS mutations are common in CRC and are associated with poor prognosis and treatment resistance.
• Patient-derived organoids offer a valuable preclinical model for studying CRC heterogeneity.

Purpose of the Study:

• To evaluate the efficacy of RAS pathway inhibitors and drug combinations in CRC organoids.
• To investigate the role of mutant RAS in resistance to targeted therapies.
• To assess the therapeutic potential of dual EGFR-MEK-ERK pathway inhibition in RAS-mutant CRC.

Main Methods:

• Generation of a panel of CRC organoids with wild-type or mutant RAS, including CRISPR-engineered KRAS mutations.
• Evaluation of RAS pathway inhibitors and drug combinations in vitro using the organoid panel.
• In vivo assessment of drug response in xenotransplanted RAS-mutant organoids.

Main Results:

• Mutant RAS strongly correlated with resistance to targeted therapies in both normal and tumorigenic CRC organoids.
• Dual inhibition of the EGFR-MEK-ERK pathway induced transient cell-cycle arrest, not cell death, in RAS-mutant organoids.
• In vivo studies confirmed growth arrest in RAS-mutant xenografts treated with pan-HER/MEK combination therapy.

Conclusions:

• Patient-derived CRC organoid libraries are effective tools for preclinical evaluation of targeted therapies.
• Mutant RAS is a key determinant of resistance to current RAS pathway inhibitors.
• Combined EGFR-MEK-ERK inhibition may offer a strategy for managing RAS-mutant CRC by inducing growth arrest.