Targeting TRK family proteins in cancer

Khotskaya, Yekaterina B.; Holla, Vijaykumar R.; Farago, Anna F.; Mills Shaw, Kenna R.; Meric-Bernstam, Funda; Hong, David S.

doi:10.1016/j.pharmthera.2017.02.006

Cited by 292Cancer Mechanisms and TherapyLung Cancer Treatments and MutationsCancer Genomics and Diagnostics

Targeting TRK family proteins in cancer

Khotskaya, Yekaterina B., Holla, Vijaykumar R., Farago, Anna F., Mills Shaw, Kenna R., Meric-Bernstam, Funda, Hong, David S.·2017·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2017.02.006

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Abstract

The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.

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Activated mutations within the Ras/Raf/MAPK/ERK pathway represent the most frequent oncogenic factor for many cancers.
“Activated mutations within this pathway represent the most frequent oncogenic factor for many cancers (Khotskaya et al. 2017).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Khotskaya et al. 2017

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Authors: Khotskaya, Y. B., Holla, V. R., Farago, A. F., Mills Shaw, K. R., Meric-Bernstam, F., & Hong, D. S.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Massachusetts General Hospital (US)
Corresponding author: Hong, David S.
ORCID: Holla, Vijaykumar R.
Farago, Anna F.
Hong, David S.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2017-05
Volume: 173
Pages: 58-66
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2017.02.006
OpenAlex: W2584455808
Cited by: 292
References: 100
Citations by year: 2026: 17 · 2025: 23 · 2024: 39 · 2023: 27 · 2022: 34 · 2021: 35 · 2020: 37 · 2019: 32 · 2018: 38 · 2017: 10
FWCI: 5.15
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Funders: The Cancer Prevention and Research Institute of Texas (RP1100584)
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
MD Anderson Cancer Center Support Grant (P30 CA016672)
NCATS (UL1 TR000371)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: NTRK gene fusions, TRK inhibitors, entrectinib, neurotrophin signaling, PI3K signaling, basket trials, orphan drug designation, lung cancer, colorectal cancer, targeted cancer therapy
MeSH terms: Animals, Antineoplastic Agents, Benzamides, Humans, Indazoles, Neoplasms, Pyrazoles, Pyrimidines, Drug Design, Receptor, trkC, Receptor, trkB, Receptor, trkA, Protein Kinase Inhibitors, Molecular Targeted Therapy

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Targeting TRK family proteins in cancer

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