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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].

Second generation TRK inhibitors such as selitrectinib and repotrectinib have been developed to overcome resistance to first line products. However, recent clinical observations indicate that resistance to second generation of TRK inhibitors that is mediated by TRK xDFG mutations, also develops [4]. The xDFG residue maps immediately N-terminal to the DFG motif, an evolutionary conserved triad across most kinases whose orientation defines the conformational states adopted by kinases. TRK xDFG substitutions represent liability common to type I TRK inhibitors i.e., those that bind to the active protein kinase confirmation. The majority of kinase inhibitors, whether TRK or other, in the clinical to date are type I.

Importantly for the design of novel inhibitors, xDFG substitutions appear to represent a potential biomarker for sensitivity to type II inhibitors i.e., drugs that bind to and stabilize the inactive conformations of TRK kinases and prevent their transition into the active state. Some of the multikinase inhibitors in the clinic (e.g., cabozantinib and ponatinib) are type II inhibitors and have been shown to reverse xDFG substitutions mediated 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.
  4. Cocco E, Lee JE, Kannan S, Schram AM, Won HH, Shifman S, Kulick A, Baldino L, Toska E, Arruabarrena-Aristorena A, Kittane S, Wu F, Cai Y, Arena S, Mussolin B, Kannan R, Vasan N, Gorelick AN, Berger MF, Novoplansky O, Jagadeeshan S, Liao Y, Rix U, Misale S, Taylor BS, Bardelli A, Hechtman JF, Hyman DM, Elkabets M, de Stanchina E, Verma CS, Ventura A, Drilon A, Scaltriti M. TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors. Cancer Discov. 2021; 11(1):126-141.

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