Testing for TRK and Other Emerging Targeted Therapy Driven Approaches in Head and Neck Cancers

 

Presented by Justin Bishop

This event is supported by an educational grant from Bayer
5' upstream gene partner
3' NTRK1, NTRK2, or NTRK3

NTRK Gene Fusions

NTRK gene fusions are targetable driver genomic alterations. These code for fusion proteins and drive tumorigenesis [1-3].

All identified NTRK gene fusions involve joining of the 3’ region of the NTRK gene, including the kinase domain, with the 5’ region of a different gene (i.e. the fusion partner) by intra- or inter-chromosomal rearrangement [1, 4].

The protein resulting from transcription and translation of the fusion is a chimeric oncoprotein. This oncoprotein is characterised by ligand-independent continual activation and overexpression of the TRK protein kinase [1, 4]. The TRK protein kinase domain is always present in TRK fusion proteins [1]. In contrast, the transmembrane domain is not present in all TRK protein fusions, suggesting it is not required for kinase activation but perhaps has a different function (e.g. cellular localisation) [1].

The resulting fusion protein is oncogenic and results in constitutive activation of signalling pathways including the MAPK, PI3K and PKC pathway [5].

 

TRK Fusion Protein Structure

Transmembrane domain
Tyrosine kinase domain
COOH
The transmembrane domain of the TRK protein is only present in select fusions
COOH

References

Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
Stransky N, Cerami E, Schalm S et al. The landscape of kinase fusions in cancer. Nat Commun 2014; 5: 4846.
Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol 2018; 11: 78.
Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016; 1: e000023.
Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5: 25-34.

Full Slide Pathology

Targeting NTRK Gene Fusions

 

Frequency and Sites of NTRK Gene Fusions in Adults and Pediatric Cancers

Cancers enriched for TRK fusions

Frequency >90%

MASC

Secretory breast carcinoma

Cellular and mixed congential mesoblastic nephoroma

Infantile fibrosarcoma

Cancers harbouring TRK fusions at lower frequencies

Frequency 5% - 25%

Gastrointestional stromal tumor (pan-negative)

Thyroid cancer

Spitzoid tumors

Frequency <5%

Acute lymphoblastic leukaemia, acute myeloid leukaemia, histiocytosis, multiple myeloma and dendritic cell neoplasms

Infantile Sarcoma

Breast Cancer

Colorectal cancer

Cholangiocarcinoma

High-grade glioma

Head and neck cancer

Lung cancer

Pancreatic cancer

Renal cell carcinoma

Sarcoma