Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Entrectinib is a pan-TRK kinase inhibitor investigated for various cancers, including colorectal cancer.
• A patient with metastatic colorectal cancer and an LMNA-NTRK1 rearrangement showed initial response to entrectinib, followed by resistance.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying acquired resistance to entrectinib in a patient with colorectal cancer.
• To identify specific genetic alterations conferring resistance to entrectinib treatment.

Main Methods:

• Longitudinal analysis of circulating tumor DNA (ctDNA).
• Xenopatient model using patient-derived tumor xenografts in mice treated with entrectinib.
• Genetic profiling of ctDNA and xenopatient samples.
• Biochemical and pharmacologic assays to assess kinase sensitivity.

Main Results:

• Acquisition of two point mutations in the NTRK1 catalytic domain, p.G595R and p.G667C, was identified in both ctDNA and xenopatient samples.
• Both p.G595R and p.G667C mutations were confirmed to confer TRKA kinase insensitivity to entrectinib.
• These findings demonstrate the utility of xenopatient and liquid biopsy analyses for tracking resistance mechanisms.

Conclusions:

• Xenopatient and liquid biopsy analyses can identify drug resistance mechanisms concurrently with patient treatment.
• p.G595R and p.G667C TRKA mutations are novel drivers of acquired resistance to entrectinib in NTRK1-rearranged colorectal cancers.
• These identified mutations provide a basis for designing next-generation TRKA inhibitors.