Journal article
Targeting TRK: A fast-tracked application of precision oncology and future directions
Critical reviews in oncology/hematology, Vol.165, pp.103451-103451
09/2021
DOI: 10.1016/j.critrevonc.2021.103451
PMID: 34389458
Abstract
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•Recurrent fusion events involving the NTRK genes occur in a wide array of cancers.•Entrectinib and larotrectinib induce responses in the majority of NTRK + tumors.•Innovative clinical basket trials led to cancer agnostic accelerated approvals.•Secondary kinase domain mutations are a frequent cause of acquired resistance.•Second-generation inhibitors avoid steric clash, overcoming resistance mutations.
The NTRK genes encode the tropomyosin-related receptor tyrosine kinases TrkA, TrkB and TrkC. TRK receptors regulate the proliferation, differentiation, and survival of many neuronal and non-neuronal glial cells during embryogenesis, thus playing a critical role in synaptic plasticity and the development of nociceptive pathways. Recurrent genomic alterations in NTRK genes, typically fusions involving the 3′ region encoding the kinase domain juxtaposed to 5′ sequences from numerous partner genes, occur at a low frequency in a wide diversity of adult and pediatric cancers. The contributions of the resulting constitutively activated kinase to oncogenesis and cancer progression are being elucidated. Larotrectinib and entrectinib are potent first-generation TRK inhibitors with IC50 values in the nanomolar range across cancer cell lines harboring NTRK fusions. Larotrectinib is highly selective for TRK receptors, whereas entrectinib also potently inhibits ROS1 and ALK. Clinical trials of both drugs demonstrated significant and durable responses in patients with tumors harboring NTRK alterations, leading to first of its kind cancer agnostic FDA approvals in the United States for drugs targeting a genomic alteration. Unfortunately, acquired resistance inevitably develops. The second-generation TRK inhibitors selitrectinib and repotrectinib are designed to overcome known mechanisms of resistance.
Details
- Title: Subtitle
- Targeting TRK: A fast-tracked application of precision oncology and future directions
- Creators
- Arsenije Kojadinovic - Icahn School of Medicine at Mount SinaiBahar Laderian - Cleveland ClinicPrabhjot S. Mundi - Columbia University Irving Medical Center
- Resource Type
- Journal article
- Publication Details
- Critical reviews in oncology/hematology, Vol.165, pp.103451-103451
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.critrevonc.2021.103451
- PMID
- 34389458
- ISSN
- 1040-8428
- eISSN
- 1879-0461
- Language
- English
- Date published
- 09/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984691514802771
Metrics
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