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Ref Type Journal Article
PMID (28676215)
Authors Zhu VW, Cui JJ, Fernandez-Rocha M, Schrock AB, Ali SM, Ou SI
Title Identification of a novel T1151K ALK mutation in a patient with ALK-rearranged NSCLC with prior exposure to crizotinib and ceritinib.
Journal Vol Issue Date Pages Journal Short Title
Lung cancer (Amsterdam, Netherlands) 110 2017 08 32-34 Lung Cancer
URL
Abstract Text Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) derive significant clinic benefit from treatment with ALK inhibitors. Crizotinib was the first approved tyrosine kinase inhibitor (TKI) for this distinct molecular subset of NSCLC. Disease progression on TKI inevitably arises secondary to diverse resistance mechanisms among which emergence of secondary ALK mutations is one of many ways in which tumor cells have adapted to survive. Therefore there is a clinical imperative to identify acquired ALK mutations via repeat tissue biopsy if clinically feasible. If such is present, switching to a different TKI with known clinical activities against the emergent resistance mutation (s) may pose a viable treatment option. Here we report for the first time a novel ALK T1151K mutation in a patient with metastatic ALK-rearranged NSCLC who progressed on crizotinib and then ceritinib. The co-crystal structure of ceritinib/ALK demonstrates a strong interaction between ceritinib and the P-loop which is facilitated by T1151 on the β3 sheet, a feature not present in the alectinib/ALK or lorlatinib/ALK co-crystal structure. It is predicated that the T1151K mutation weakens these interactions leading to drug resistance, or causes conformational changes of the ALK catalytic domain resulting in higher affinity for ATP and therefore diminished inhibitor binding. We conclude that the T1151K ALK mutation confers resistance to ceritinib, which may be rescued by alectinib or lorlatinib as evidenced by this clinical narrative.

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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 T1151K missense unknown ALK T1151K lies within the protein kinase domain of the Alk protein (UniProt.org). T1151K has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 28676215, PMID: 30519133), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
ALK T1151M missense gain of function - predicted ALK T1151M lies within the protein kinase domain of the Alk protein (UniProt.org). T1151M is not transforming (PMID: 18923525, PMID: 33674381, PMID: 25517749) and does not induce Alk phosphorylation in culture (PMID: 18923525), but is activating in in vitro assays (PMID: 33674381, PMID: 25517749), and has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 28676215, PMID: 27009859), and therefore, is predicted to lead to a gain of Alk protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK T1151K lung adenocarcinoma predicted - resistant Ceritinib Case Reports/Case Series Actionable In a clinical case study, ALK T1151K was identified in the post-progression biopsy of a patient with lung adenocarcinoma harboring EML4-ALK after Xalkori (crizotinib) and Zykadia (ceritinib) therapies (PMID: 28676215). 28676215
EML4 - ALK ALK T1151K lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, ALK T1151K was identified in the post-progression biopsy of a patient with lung adenocarcinoma harboring EML4-ALK after Xalkori (crizotinib) and Zykadia (ceritinib) therapies (PMID: 28676215). 28676215