Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	71	14	2011 Jul 15	4920-31	Cancer Res

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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Molecular Profile	Treatment Approach
EML4 - ALK ALK L1196M	Ensartinib
EML4 - ALK ALK C1156Y	Ensartinib

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Ensartinib	Ensartinib	45	8
X-376	X-376	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ensartinib		X-396	ALK Inhibitor 32	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 32	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, Aug 2024).	Y
ALK	L1196M	missense	gain of function	ALK L1196M lies within the protein kinase domain of the Alk protein (UniProt.org). L1196M results in increased Alk kinase activity (PMID: 30258533), modest Alk autophosphorylation, and transformation in cell 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	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	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
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 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 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