Overcoming TRK Resistance: The Efficacy of FCN-098 in Targeting Cancer Cells

Tropomyosin receptor kinases (TRKs), activated by neurotrophins, are implicated in the regulation of neuronal cell differentiation and survival. Abnormal TRK pathway activation due to gene fusions is linked to poor prognoses in various solid tumors. While first-generation TRK inhibitors like larotrectinib and entrectinib have shown efficacy, resistance mutations can diminish their effectiveness. This has necessitated the development of second-generation TRK inhibitors capable of overcoming such resistance.

FCN-098 is a second-generation TRK inhibitor that has shown significant kinase inhibition activity against both wild-type and mutant TRKs within the sub-nano or single nanomolar range. It has effectively inhibited TRK phosphorylation and its downstream signaling in TRK fusion-positive cancer cells, as well as suppressed the proliferation of these cells without affecting TRK-negative cell lines.

In xenograft models, FCN-098 exhibited substantial anti-tumor activity against tumors driven by both wild-type and mutant TRK fusions. Its anti-tumor efficacy was found to be superior to LOXO-195 in certain xenograft models and comparable in others. FCN-098 also demonstrated favorable pharmacokinetic properties and safety in non-clinical studies, with a longer half-life, higher maximum concentration, and larger area under the curve in dogs compared to LOXO-195.

The study concludes that FCN-098 has the potential to be a promising therapeutic option for a broad spectrum of solid tumors with TRK fusions, offering a new approach to treating cancers that have developed resistance to existing TRK inhibitors.