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Ref Type Journal Article
PMID (21613408)
Authors Lovly CM, Heuckmann JM, de Stanchina E, Chen H, Thomas RK, Liang C, Pao W
Title Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.
Journal Cancer research
Vol 71
Issue 14
Date 2011 Jul 15
URL
Abstract Text Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Ensartinib Ensartinib 21 8
X-376 X-376 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ensartinib X-396 ALK Inhibitor 23 Ensartinib (X-396) is a small molecule inhibitor of ALK, which inhibits downstream signaling and potentially leads to decreased growth of ALK-expressing tumors (PMID: 21613408, PMID: 31628085).
X-376 ALK Inhibitor 23 X-376 is a small molecule inhibitor of Alk, which may reduce growth of ALK-driven tumor cells (PMID: 21613408).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK C1156Y missense unknown ALK C1156Y lies within the protein kinase domain of the Alk protein (UniProt.org). C1156Y has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 21613408, PMID: 20979473, PMID: 27490033, PMID: 27045755), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2020). Y
ALK L1196M missense gain of function - predicted ALK L1196M lies within the protein kinase domain of the Alk protein (UniProt.org). L1196M is predicted to confer a gain of function to the Alk protein as demonstrated by transformation activity and modest autophosphorylation of Alk in culture (PMID: 25517749), and confers resistance to Alk inhibitors in the context of ALK rearrangements in culture and in vivo (PMID: 21613408, PMID: 25421750, PMID: 31452835). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK C1156Y Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK ALK C1156Y were insensitive to Xalkori (crizotinib) as demonstrated by lack of growth inhibition and lack of kinase inhibition in culture (PMID: 21613408). 21613408
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive Ensartinib Preclinical Actionable In a preclinical study, Ensartinib (X-396) inhibited growth and Alk phosphorylation in cells expressing the Xalkori (crizotinib) resistance mutation, EML4-ALK C1156Y (PMID: 21613408). 21613408
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Ensartinib Preclinical Actionable In a preclinical study, Ensartinib (X-396) inhibited growth and Alk phosphorylation in cells expressing the Xalkori (crizotinib) resistance mutation, EML4-ALK ALK L1196M (PMID: 21613408). 21613408
EML4 - ALK lung non-small cell carcinoma sensitive Ensartinib + Sirolimus Preclinical Actionable In a preclinical study, transformed non-small cell lung cancer cells harboring EML4-ALK demonstrated enhanced growth inhibition to a combination treatment with Afinitor (sirolimus) and Ensartinib (X-396) (PMID: 21613408). 21613408
EML4 - ALK lung cancer sensitive X-376 Preclinical - Cell line xenograft Actionable In a preclinical study, X-376 inhibited Alk signaling, resulted in growth inhibition in lung cancer cells harboring EML4-ALK fusion in culture and in cell line xenograft models (PMID: 21613408). 21613408