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|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|EML4 - ALK ALK C1156Y||Ensartinib|
|EML4 - ALK ALK L1196M||Entrectinib|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK ALK L1196M||Advanced Solid Tumor||conflicting||Entrectinib||Preclinical - Cell culture||Actionable||In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M were sensitive to Rozlytrek (entrectinib), resulting in anti-proliferative activity in culture (PMID: 26939704).||26939704|
|EML4 - ALK ALK G1269A||Advanced Solid Tumor||predicted - resistant||Entrectinib||Preclinical - Cell culture||Actionable||In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A demonstrated a decreased response when treated with Rozlytrek (entrectinib) compared to cells expressing wild-type EML4-ALK (PMID: 26939704).||26939704|
|EML4 - ALK||lung non-small cell carcinoma||sensitive||Entrectinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, non-small cell lung carcinoma cells harboring EML4-ALK were sensitive to Rozlytrek (entrectinib), resulting in inhibition of cell proliferation and complete tumor regression in cell line xenograft models (PMID: 26939704).||26939704|
|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 Rozlytrek (entrectinib) 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 Rozlytrek (entrectinib), resulting in anti-proliferative activity (PMID: 26939704).||26939704|