Fig. 4: Inhibitory potential of larotrectinib and altiratinib on NTRK1 gatekeeper and xDFG mutations.
From: NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors
Dose-response cell viability data comparing Ba/F3 cells expressing wildtype TPM3-NTRK1 or kinase domain mutants (V573M, F589L, G667C, and G67S) that were treated with larotrectinib (a) or altiratinib (b) for 72 h. Representative data are average ± standard error of means (SEM) from three independent replicates. c Column graph shows IC50 for indicated Ba/F3 cell lines treated with larotrectinib (teal bars) or altiratinib (gray bars). Y-axis depicts data on the log[10] scale. d Immunoblot analysis of TPM3-NTRK1 wildtype and mutants autophosphorylation (pNTRK), Erk1/2 (pErk1/2) phosphorylation, and corresponding total Erk2 and loading control (Gapdh) levels. “Veh.” indicates vehicle (DMSO) treatment. e–g Molecular docking of larotrectinib (top panel) or altiratinib (bottom panel) onto NTRK1 wildtype (left panel—wildtype amino acid) or mutant (right panel—mutated amino acid) structures. h Tumor volume as a function of time from mice bearing Ba/F3-TPM3-NTRK1F589L allograft tumors that were treated with vehicle, larotrectinib (100 mg/kg, BID) or altiratinib (50 mg/kg, BID). Treatment (Tx) was initiated 7 days after implantation (black arrow). i Area under the curve analysis to compare the efficacy of larotrectinib and altiratinib in TPM3-NTRK1F589L tumors to vehicle-treated tumors (average ± standard error of means (SEM)). Statistically significant differences as shown with asterisk and p values above respective columns. j Animal weight (grams (g)) measured during treatment with vehicle, larotrectinib and altiratinib.
