Mechanisms of TRK Protein Activation in Cancer

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The following table summarises how oncogenic activation of TRK proteins can arise.

Table 1: Mechanisms of TRK Protein Activation

Mutations The effect of the majority of NTRK gene mutations on tumourigenesis and progression has not been determined [1]. However, some point mutations (NTRK1 p. G667C, NTRK3 p. G696A) may arise from acquired resistance   to TRK inhibitors [2].
Splice variants NTRK gene splice variants have been detected in neuroblastoma and acute myeloid leukaemia [1].
Gene fusions These are the most common mechanisms of oncogenic activation of NTRK genes [1] and currently the most promising aberration for use as a therapeutic target.

References

  1. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
  2. Okamura R, Boichard A, Kato S et al. Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. JCO Precis Oncol 2018; 2018.

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Last update: 24 June 2019