A Subset of Patients Develops Off-Target Mechanisms of Resistance to TRK Inhibition

Resistance mediated by genomic alterations implicated in the MAPK pathway described

A group of researchers from the Memorial Sloan Kettering Cancer Center in New York, NY, USA led by Alexander Drillon and Maurizio Scaltriti reported in the letter published on 12 August in the Nature Medicine about off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic acquisition of mitogen-activated protein kinase (MAPK) pathway-activating alterations. The findings have potential implications for clinical management and future clinical trial design, as these patients may benefit from combined targeted therapy.

TRK fusions are found in a variety of cancer types. They lead to oncogenic addiction, and strongly predict tumour-agnostic efficacy of TRK inhibition.

With recent approvals of the selective TRK inhibitors for the treatment of patients with any TRK fusion-positive adult or paediatric solid tumour, identification of mechanisms of treatment failure after initial response has become a question of therapeutic relevance.

However, the authors reported that so far, the only known resistance mechanism was the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors 

In their paper, the study team reported off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the MAPK pathway 

In particular, targeted therapy directed to MAPK pathway, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modelling further suggested that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations.

The authors concluded that their data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical study design.

All genomic results and associated clinical data for all patients in this study are publically available in the cBioPortal for Cancer Genomics

The study was funded by the US National Cancer Institute (NCI) under the MSKCC Support Grant/Core Grant. This work was also partially funded by the Cycle for Survival and LOXO Oncology. The study was also supported by the NIH grant.

 

Reference

Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nature Medicine; Published online 12 August 2019. doi: 10.1038/s41591-019-0542-z.