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      Case report: Acquired neurotrophic tyrosine receptor kinase inhibitor resistance in a patient with pancreatic neuroendocrine carcinoma receiving entrectinib

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          Abstract

          Pancreatic neuroendocrine carcinoma (panNEC) is a rare disease. The rearrangements of neurotrophic tropomyosin receptor kinase (NTRK) genes are oncogenic. And in the existed literatures, the prevalence of NTRK3 was only 0.1% in neuroendocrine tumors. NTRK inhibitor was approved for refractory and recurrence NTRK fusion-positive solid tumors did not respond to standard treatment. We described a patient with panNEC who was confirmed to have ETV6-NTRK3 fusion gene by liquid biopsy. The patient initially responded well to entrectinib, a first-generation NTRK inhibitor, but developed resistance with two acquired NTRK3-G623R and NTRK3-G623E mutations detected by a second liquid biopsy. Kirsten rat sarcoma vial oncogene (KRAS) K117N mutation was found initially but became undetectable after resistance. This was the first report demonstrating the novel agent, entrectinib, used for the NTRK3-fusion gene found by the liquid biopsy in panNEC. Our report provides evidence of not only the effectiveness but also the acquired resistance of entrectinib. Also, we highlighted the potential role of genomic sequencing after entrectinib failure. Furthermore, liquid biopsy should be considered if acquiring tissue from the patient is challenging. Further studies regarding NTRK inhibitors in panNEC were needed.

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          Most cited references12

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          NTRK fusion-positive cancers and TRK inhibitor therapy

          NTRK gene fusions involving either NTRK1 , NTRK2 , or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB, and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.
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            Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations

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              Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

              Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                10 January 2023
                2022
                : 12
                : 1031396
                Affiliations
                [1] 1 Department of Oncology, Taipei Veterans General Hospital , Taipei, Taiwan
                [2] 2 Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital , Taipei, Taiwan
                [3] 3 Division of Hematology, Department of Medicine, Taipei Veterans General Hospital , Taipei, Taiwan
                [4] 4 School of Medicine, National Yang Ming Chiao Tung University , Taipei, Taiwan
                Author notes

                Edited by: Zhongqiu Wang, Affiliated Hospital of Nanjing University of Chinese Medicine, China

                Reviewed by: Haruhiko Sugimura, Hamamatsu University School of Medicine, Japan; Hemant Gujar, University of Southern California, United States

                *Correspondence: Wen-Chi Wu, wcwu6@ 123456vghtpe.gov.tw

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.1031396
                9871888
                36703785
                ac4f9f0c-2161-486f-9818-00896047c323
                Copyright © 2023 Wu and Chen

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 August 2022
                : 20 December 2022
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 12, Pages: 5, Words: 1667
                Funding
                Funded by: Taiwan Cancer Clinic Foundation , doi 10.13039/100018002;
                This work was in part financially supported by the “Taiwan Cancer Clinic Foundation” and “Melissa Lee Cancer Foundation” of the Taipei, Taiwan. The funders have no role in study design, data collection, analysis, and interpretation, or in writing of the manuscript.
                Categories
                Oncology
                Case Report

                Oncology & Radiotherapy
                entrectinib,neurotrophic tropomyosin receptor kinase (ntrk),pancreatic neuroendocrine carcinoma (pannec),liquid biopsy,repotrectinib

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