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Resistance to TRK inhibition by larotrectinib and entrectinib can occur through the development of NTRK gene mutations, which involves amino acid substitutions in the solvent-front, gatekeeper residues of the NTRK genes (NTRK1 p. G667C, NTRK3 p. G696A) and xDFG motif substitutions [1, 2]. More recently, other genomic MAPK pathway alterations including BRAF p. V600E mutation, KRAS p. G12D mutation, and MET amplification have been shown to be acquired mechanisms of resistance to TRK inhibitor therapy[3].

Additional TRK inhibitors such as BAY 2731954 (LOXO-195) and repotrectinib are being developed to overcome these mechanisms of resistance.


  1. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
  2. Russo M, Misale S, Wei G et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer Discov 2016; 6: 36-44.
  3. Cocco E, Kulick A, Misale S et al. Resistance to TRK inhibition mediated by convergent MAP kinase pathway activation. AACR Annual Meeting, March 29-April 3, 2019, Atlanta, Georgia 2019; Abstract LB-118 / 13.

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