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PMID (22034911)
Authors Zhang S, Wang F, Keats J, Zhu X, Ning Y, Wardwell SD, Moran L, Mohemmad QK, Anjum R, Wang Y, Narasimhan NI, Dalgarno D, Shakespeare WC, Miret JJ, Clackson T, Rivera VM
Title Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.
Journal Chemical biology & drug design
Vol 78
Issue 6
Date 2011 Dec
URL
Abstract Text Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib-resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK-positive non-small-cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib's narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance.

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Molecular Profile Treatment Approach
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
ALK G1269S missense gain of function - predicted ALK G1269S lies within the protein kinase domain of the Alk protein (UniProt.org). G1269S is predicted to confer a gain of function on the Alk protein as indicated by increased phosphorylation of Alk (PMID: 21948233) and has been demonstrated to confer resistance to Alk inhibitors in the context of EML4-ALK (PMID: 21948233, PMID: 22034911). Y
ALK L1152V missense unknown ALK L1152V lies within the protein kinase domain of the Alk protein (UniProt.org). L1152V is associated with decreased ALK inhibitor sensitivity in the context of an ALK fusion in culture (PMID: 22034911), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2022).
ALK S1206R missense unknown ALK S1206R lies within the protein kinase domain of the Alk protein (UniProt.org). S1206R has been demonstrated to occur as a secondary drug resistance mutation in the context of EML4-ALK (PMID: 22034911), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Mar 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK S1206R Advanced Solid Tumor resistant Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing ALK S1206R in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture and in cell line xenograft models (PMID: 22034911). 22034911
EML4 - ALK ALK G1269S Advanced Solid Tumor resistant Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing ALK G1269S in the context of EML4-ALK were resistant to Xalkori (crizotinib) in culture and in cell line xenograft models (PMID: 22034911). 22034911