Reference Detail

Ref Type Journal Article
PMID (26939704)
Authors Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A
Title Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications.
Journal Molecular cancer therapeutics
Vol 15
Issue 4
Date 2016 Apr
URL
Abstract Text 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. Mol Cancer Ther; 15(4); 628-39. ©2016 AACR.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
ETV6 - NTRK2 fusion gain of function - predicted ETV6-NTRK2 results in the fusion of ETV6 and NTRK2 (PMID: 26939704). ETV6-NTRK2 has not been biochemically characterized, but is sensitive to Trk inhibition (PMID: 26939704, PMID: 26884591), and therefore, is predicted to result in a gain of function.
ETV6 - ROS1 fusion gain of function - predicted ETV6-ROS1 results from the fusion of ETV6 and ROS1, and leads to constitutive ROS1 activation in cultured cells (PMID: 26939704) and therefore, is predicted to confer a gain of function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4-ALK ALK G1202R Advanced Solid Tumor resistant Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R were resistant to RXDX-101 (PMID: 26939704). 26939704
ETV6-NTRK3 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK3 were sensitive to Entrectinib (RXDX-101), resulting in inhibition of cell proliferation in culture (PMID: 26939704). 26939704
NPM1-ALK anaplastic large cell lymphoma sensitive Entrectinib Preclinical - Cell line xenograft Actionable In a preclinical study, anaplastic large cell lymphoma cells harboring NPM1-ALK were sensitive to Entrectinib (RXDX-101) in culture and in cell line xenograft models, resulting in inhibition of NPM1-ALK autophosphorylation and near complete tumor regression (PMID: 26939704). 26939704
EML4-ALK ALK L1196M Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M were sensitive to Entrectinib (RXDX-101), resulting in anti-proliferative activity in culture (PMID: 26939704). 26939704
ETV6-NTRK2 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK2 were sensitive to Entrectinib (RXDX-101), resulting in inhibition of cell proliferation in culture (PMID: 26939704). 26939704
ETV6-ROS1 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing ETV6-ROS1 were sensitive to Entrectinib (RXDX-101), resulting in inhibition of cell proliferation in culture and decreased tumor growth in xenograft models (PMID: 26939704). 26939704
EML4-ALK ALK G1269A Advanced Solid Tumor decreased response Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A demonstrated a decreased response when treated with Entrectinib (RXDX-101) compared to cells expressing wild-type EML4-ALK (PMID: 26939704). 26939704
ETV6-ALK Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-ALK demonstrated sensitivity to Entrectinib (RXDX-101) in culture (PMID: 26939704). 26939704
EML4-ALK ALK C1156Y Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK C1156Y were sensitive to Entrectinib (RXDX-101), resulting in anti-proliferative activity (PMID: 26939704). 26939704
EML4-ALK non-small cell lung carcinoma sensitive Entrectinib Preclinical - Cell line xenograft Actionable In a preclinical study, non-small cell lung carcinoma cells harboring EML4-ALK were sensitive to Entrectinib (RXDX-101), resulting in inhibition of cell proliferation and complete tumor regression in cell line xenograft models (PMID: 26939704). 26939704