Resistance to TRK inhibition mediated by convergent MAPK pathway activation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Tropomyosin receptor kinase (TRK) fusions drive various cancers and predict response to TRK inhibitors like larotrectinib.
• Identifying resistance mechanisms is crucial following the approval of TRK inhibitors for solid tumors.

Purpose of the Study:

• To investigate novel mechanisms of resistance to TRK inhibitors beyond known on-target mutations.
• To explore the role of the mitogen-activated protein kinase (MAPK) pathway in TRK inhibitor resistance.

Main Methods:

• Analysis of genomic alterations in patients and patient-derived models treated with TRK inhibitors.
• Assessment of MAPK pathway activation as a resistance mechanism.
• Evaluation of MAPK pathway-directed therapies, alone or in combination with TRK inhibitors.

Main Results:

• Identified off-target resistance mediated by genomic alterations activating the MAPK pathway.
• Demonstrated that MAPK pathway-targeted therapy, alone or combined with TRK inhibition, restored disease control.
• Experimental models suggest upfront dual TRK and MEK inhibition may delay progression in susceptible cancers.

Conclusions:

• Off-target resistance via MAPK pathway activation is a significant mechanism of failure for TRK inhibitors.
• Targeting the MAPK pathway offers a therapeutic strategy to overcome TRK inhibitor resistance.
• These findings have implications for clinical management and the design of future clinical trials for TRK fusion-positive cancers.