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NTRK Gene Fusions: Novel Targets for Tumor-Agnostic Cancer Therapy

Published: Wednesday, Jun 20, 2018
Over the past few decades, our knowledge of the role of gene mutations in oncogenesis has transformed cancer care.1 Advanced sequencing techniques have revolutionized our understanding of how cancer has developed and enabled treatment selection based on genomic characterization of the tumor.2 An actionable mutation or genomic event refers to a detected DNA change that predicts a patient's treatment response to a particular agent. An actionable mutation may be an oncologic driver, or it may be relevant to a target that can be inhibited pharmacologically.2 Assessing response to a drug among a molecularly defined patient subset across cancer types is increasingly common with the use of umbrella or basket trials.2 In 2017, the FDA approved the first oncologic therapy based on genomic biomarkers independent (or agnostic) of cancer site or histology.3

Gene Fusions in Malignancies

The discovery and targeting of gene fusions was an important oncologic breakthrough in the last century.4 Gene fusions arise from genomic rearrangements, which include chromosomal inversions, duplications, deletions, or translocations.4

Gene fusions were first discovered in the 1970s in patients with chronic myeloid leukemia, from whom circulating tumor cells containing the t(9;22)(q34;q11) translocation were identified.4 Interchromosomal translocations were subsequently recognized in salivary gland adenomas, such as t(3;8)(p21;q12), and sarcomas, such as t(11:22)(p24;q12).4 In the decade after these discoveries, gene fusions were increasingly described in solid tumors.5 As of February 2018, 11,207 gene fusions have been identified in more than 68,000 patient cases of malignancies.6

Oncogenic Mechanisms of Gene Fusions

Gene fusions may serve as drivers for both cancer development and progression.4 Chromosomal rearrangements can lead to the fusion of 2 genes, creating chimeric proteins that serve as strong oncogenic drivers.4 The mechanisms by which oncogenic fusions lead to cancer development or progression may include altered transcription and constitutive kinase activation.

Altered Transcription

Altered transcription is one mechanism by which a gene fusion event may drive oncogenesis.4 A fusion event may involve a transcription factor.4 For example, in prostate cancer, the TMPRSS2-ERG fusion protein decreases expression of the androgen receptor, in addition to inhibiting existing androgen receptors, and leads to the disruption of cell differentiation, resulting in the selection for non- androgen-dependent cellular proliferation.4 Altered transcription may also result from the fusion of a promoter to a proto-oncogene, augmenting its expression, as in COL1A1-PDGFB fusion in dermatofibrosarcoma protuberans.4

Constitutive Kinase Activation in Kinase Fusions

Kinase fusions are commonly targeted oncogenic mechanisms. The fusion of 2 genes can result from chromosomal rearrangements, creating chimeric proteins that are strong oncogenic drivers. One partner in these types of fusions is often a kinase.4 Signal transduction in eukaryotic cells is mostly mediated by protein kinases.7 Through protein phosphorylation, kinases play a critical role in intercellular communication and in mediating physiological responses.7 Protein kinases control many cellular processes by modifying substrate activity. These cellular processes include transcription, cell cycle progression, apoptosis, and differentiation, to name a few.7 During genomic fusion events, the kinase activity is often preserved. Hence, kinase fusions result in constitutive activation and amplified downstream signaling.4 Tyrosine kinase fusions, including ALK, NTRK1/2/3, ROS1, and RET have been identified in a variety of cancer types.4,8

Serine-threonine kinase fusions, including those involving BRAF, CRAF, and MAST1/2, have also been reported.4,8 These kinase fusions lead to amplified signaling in pathways involved in cell growth and survival.4

 

Figure 1. TRK Receptor Signaling10

Figure 1. TRK Receptor Signaling10
AKT indicates v-akt murine thymoma viral oncogene homologue (also known as protein kinase B); BDGF, brainderived growth factor; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; GAB1, GRB2-associated protein 1; GRB2, growth factor receptor-bound protein 2; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor; NTF-3, neurotrophin 3; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; RAF, rapidly accelerated fibrosarcoma kinase; RAS, rat sarcoma kinase; SHC, Src homology 2 domain.

Reprinted with permission. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. doi:10.1136/esmoopen-2015-000023.

 
A number of tyrosine kinase inhibitors have been developed or are in development. 4 The majority of these compounds are multikinase inhibitors with activity against more than 1 kinase.4 One of these kinase fusions, neurotrophic tropomyosin receptor kinase (NTRK) gene rearrangement, has emerged as a novel target for cancer therapy.

Tropomyosin Receptor Kinase Family

The tropomyosin receptor kinase (TRK) receptor family consists of 3 transmembrane proteins: TRKA, TRKB, and TRKC receptors. TRKA is encoded by the NTRK1 gene, whereas TRKB is encoded by the NTRK2 gene, and TRKC by the NTRK3 gene.9


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