Fig. 2: Solvent front mutation TPM3-NTRK1G595R but not ETV6-NTRK3G623R is completely resistant to type I larotrectinib and type II altiratinib inhibitors.
From: NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors
Cell viability data for Ba/F3 cells expressing TPM3-NTRK1G595R (a) or ETV6-NTRK3G623R (b) fusions treated with larotrectinib or altiratinib at the indicated doses after 72 h. Representative data are average ± standard error of means (SEM) from three independent replicates. c, d Ba/F3 cells expressing TPM3-NTRK1G595R (c) or ETV6-NTRK3G623R (d) fusions were treated for 2 h with DMSO (Veh: vehicle) or the indicated concentrations (in nanomolar (nM)) of larotrectinib or altiratinib. Immunoblotting to assess TPM3-NTRK1 and ETV6-NTRK3 autophosphorylation (pNTRK), total NTRK (tNTRK), and loading control (Gapdh). Immunoblot data are representative of three independent experiments. The percent inhibition of phosphorylation is shown below the blots for select concentrations. e Molecular docking of altiratinib to structural homology models of NTRK1 and NTRK3 solvent front mutants (superimposed alignment of NTRK1 (salmon) and NTRK3 (gray) crystal structures). Green colored loop represents NTRK1 amino acids 603 to 623 and magenta-colored loop represents NTRK3 amino acids 631 to 662.
