NTRK gene fusions

Fusions of the neurotrophic tyrosine receptor kinases (NTKR) are known drivers of oncogenesis and in rare cases can also play a role in melanoma. In NTRK fusion genes, one of the three neurotrophic tyrosine kinases (NTRK-1;NTRK- 2; NTRK -3) is fused with another gene. Each of the 3 NTRK genes(NTRK1 gene, NTRK2 gene, NTRK3 gene) is located on a different chromosome and codes for a different tropomyosin receptor kinase (TRK), such as TRKA, TRKB and TRKC. Tropomyosin receptor kinases belong to the group of receptor tyrosine kinases and consist of the transmembrane proteins TRKA, B and C, which are encoded by the corresponding genes NTRK 1-3. They are primarily expressed in neuronal tissue and are important for the development of central and peripheral nervous tissue. They also play an important role in the regulation of cell survival.

Since TRK inhibitors are already available for patients with NTKR fusions, theeapeutic options could also be available for melanoma in suitable cases.

NTRK fusion genes are formed by the fusion of an NTKR gene with another independent gene due to a non-homologous end linkage during the DNA repair process. NTKR fusion genes play an important role in the development of malignant tumors. They lead to the formation of chimeric, constitutively activated tyrosine kinases, which influence the metabolism and proliferation of the tumor cell via different signaling pathways. The various NTRK genes are found at the following gene loci:

• NTRK1: Coded TrkA (gene locus 1q21-q22).
• NTRK2: Encoded TrkB (gene locus 9q22.17)
• NTRK3: Coded TrkC (gene locus 15q25.9)

NTRK fusion genes are found in various malignant tumors, including:

• colorectal carcinoma (CRC): TPM3-NTRK1, LMNA-NTRK1
• non-small cell lung cancer (NSCLC): MPRIP-NTRK1, TPM53-NTRK1, TRIM24-NTRK2
• papillary thyroid carcinoma (PTC): PPL-NTRK1, RBPMS-NTRK3
• breast carcinoma: ETV6-NTRK3
• Glioblastoma: BCAN-NTRK1, NFASC-NTRK1
• Spitzoid melanoma: NTRK fusions with a prevalence of 21-25% (Forschner A et al. 2022)
• Cutaneous melanoma. NTRK fusions with a prevalence <1% (Forschner A et al. 2022)1
• Mucosal melanoma. NTRK fusions with a prevalence <1% (Forschner A et al. 2022)

Treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumor histology. First-generation TRK inhibitors are well tolerated by most patients. The downside: NTRK fusion-positive cancers eventually become resistant to TRK inhibition in advanced stages; resistance can be acquired through the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005, which are being investigated in clinical trials (Cocco E et al. 2018).

1. Barker PA et al. (1993) Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem 268:15150-15157).
2. Forschner A et al. (2022) NTKR gene fusions in melanoma: diagnosis, prevalence and possible resistance to therapy. JDDG 18:1387-1493
3. Hempstead BL et al. (1991) High-affinity NGF binding requires co-expression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350:678-683.
4. Jing S et al. (1992) Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron 9:1067-1079