High affinity nerve growth factor receptor (NTRK1) A608D mutant (TRKA A608D)

TRKA (encoded by the NTRK1 gene) is a receptor tyrosine kinase that normally regulates neuronal development and survival by binding nerve growth factor (NGF). In various malignancies, chromosomal rearrangements result in NTRK1 gene fusions, which lead to the constitutive activation of the TRKA kinase domain and drive oncogenic signaling through pathways such as MAPK, PI3K/Akt, and PLC-gamma. The A608D mutation is a specific acquired resistance mutation that arises in the kinase domain of the TRKA fusion protein, typically following treatment with first-generation TRK inhibitors like larotrectinib and entrectinib. This mutation, often categorized alongside solvent-front mutations, alters the ATP-binding pocket and sterically hinders the binding of first-generation inhibitors, leading to disease progression. Next-generation TRK inhibitors, such as selitrectinib and repotrectinib, are designed with compact macrocyclic structures to overcome the structural interference caused by the A608D mutation, offering a therapeutic strategy for patients with resistant NTRK-positive cancers.

Other names

NTRK1 A608DTropomyosin receptor kinase A A608DTrkA A608Dp.A608DTRKA A608D mutation

Tyrosine kinase inhibition