NTRK1 Fusion in Glioblastoma Multiforme

Kim, Jin‐Kuk; Lee, Yeri; Cho, Hee Jin; Lee, Young‐Eun; An, Jaeyeol; Cho, Gye-Hyun; Ko, Young‐Hyeh; Joo, Kyeung Min; Nam, Do‐Hyun

doi:10.1371/journal.pone.0091940

Cited by 88 publications

(78 citation statements)

References 30 publications

(58 reference statements)

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“…No TRKA inhibitors were explored in clinical trials with the possible exception of lestaurtinib (CEP-701), a staurosporine-derivative multikinase inhibitor that was investigated in clinical settings with reported TRKA overexpression, without evidence of efficacy (7,38). However, recent studies that have identified recurring oncogenic NTRK1 rearrangements in subsets of NSCLC and colorectal carcinoma patients (11,12), as well as other studies suggesting a potential role of activated TRKA in other tumor types, including glioblastoma and Spitz melanoma (14)(15)(16)39), have created much renewed interest in the identification and clinical investigation of effective TRKA inhibitors (13). In a rapidly evolving scenario, these findings indicate that TRKA inhibition may represent an innovative opportunity for the therapy of selected patients whose tumors harbor NTRK1 gene rearrangements and this has supported the enrollment of TRKA-positive patients in ongoing clinical trials of entrectinib.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in a rapidly evolving landscape, large-scale sequencing efforts have led to identification of additional chromosomal rearrangements involving NTRK1 as well as NTRK2 and NTRK3, the genes which respectively encode the TRKA, TRKB, and TRKC proteins, in further tumor types (14)(15)(16)(17). These findings provide a strong rationale for the development of TRK kinase inhibitors in several distinct selected patient populations.…”

Section: Introductionmentioning

confidence: 99%

“…The recent description of recurring rearrangements of the NTRK1 gene, which encodes this kinase, in subsets of major indications such as NSCLC, colorectal carcinoma together with the identification of NTRK2 and NTRK3 rearrangements in glial tumors and inflammatory breast cancer, respectively, and perhaps additional tumor types (11,12,14,16,17), has highlighted the relevance of these kinases as pharmacologic targets and the clinical need for effective inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

248

191

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Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

248

191

View full text Add to dashboard Cite

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“…Collectively, these findings suggest that tumor cells with different NTRK1 fusion partners acquire TRK inhibitor resistance, at least in part, by common mutations that induce drug resistance. Previous studies have showed that entrectinib is clinically effective for tumors expressing NTRK1 fusion products, including NSCLC expressing SQSTN-NTRK1, glioneuronal tumors expressing BCAN-NTRK1, and colon cancer expressing LMNA-NTRK1 (5,6,39). However, almost all responders suffered from recurrent diseases due to drug resistance (5,6,39).…”

Section: Discussionmentioning

confidence: 99%

“…2). At least four NTRK1 fusion partners, such as LMNA, TPM3, SQSTM1, and BCAN, have been reported (3)(4)(5)(6). The NTRK1 fusion gene products promote signal transduction through the PI3K-AKT, PLCg-PKC, and SHC-RAS-MAPK signaling pathways and play crucial roles in cell survival (7).…”

Section: Introductionmentioning

confidence: 99%

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

Nishiyama

Yamada

Kita

et al. 2018

Clinical Cancer Research

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Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by nextgeneration sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation.Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinibresistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases. Clin Cancer Res; 1-13. Ó2018AACR.

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Neoplasms of the Breast

Tripathy¹,

Makhnoon²,

Arun³

et al. 2022

Holland‐Frei Cancer Medicine

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Overview Breast cancer is the most common cancer among women in the United States and growing in incidence worldwide, while mortality due to breast cancer is slowly decreasing. The last two decades have witnessed many changes in the diagnostic landscape both in terms of imaging studies and laboratory tests, most notably next‐generation sequencing both on tumor and blood. Our understanding of breast oncogenesis, tumor heterogeneity, and metastasis has deepened. Segmental mastectomy and sentinel lymph node (SLN) biopsy have been used in the majority of cases coupled with radiation therapy. In cases managed with mastectomy, radiation of one to three positive nodes has been utilized more often. Gene expression profiling has been used to identify women with hormone receptor‐positive (HR+) breast cancer who would benefit from adjuvant chemotherapy. Targeted therapy has been developed for HR+, HER2 amplified, and triple‐negative breast cancer. Immune checkpoint inhibitors have improved the management of triple‐negative disease. poly(adenosine diphosphate [ADP]–ribose) (PARP) inhibitors have improved outcomes for breast cancer patients with BRCA1/2 mutations. Combinations of targeted therapies and hormonal therapies have proved effective for adjuvant therapy and in recurrent disease.

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NTRK1 Fusion in Glioblastoma Multiforme

Cited by 88 publications

References 30 publications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

Neoplasms of the Breast

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