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|Ref Type||Journal Article|
|Authors||Ou SH, Milliken JC, Azada MC, Miller VA, Ali SM, Klempner SJ|
|Title||ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression.|
|Journal||Lung cancer (Amsterdam, Netherlands)|
|Abstract Text||Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. Both tumor samples had essentially the same genomic profile by comprehensive genomic profiling otherwise. This is the first patient report that demonstrates ALK F1174V mutation is sensitive to alectinib and further confirms missense acquired ALK I1171 mutation is resistant to alectinib. Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations.|
|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||I1171S||missense||unknown||ALK I1171S lies within the protein kinase domain of the Alk protein (UniProt.org). I1171S has been demonstrated to confer drug resistance in the context of ALK fusions in culture (PMID: 27009859, PMID: 25393796, PMID: 26464158), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2020).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK ALK I1171S ALK F1174V||lung non-small cell carcinoma||predicted - resistant||Alectinib||Case Reports/Case Series||Actionable||In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK and ALK F1174V initially responded to Alecensa (alectinib), but then demonstrated progression in one of two lung nodules, which was found to harbor a secondary resistance mutation, ALK I1171S, and upon resection of the nodule the patient continued Alecensa (alectinib) treatment and achieved complete remission (PMID: 26464158).||26464158|
|EML4 - ALK ALK F1174V||lung non-small cell carcinoma||predicted - sensitive||Alectinib||Case Reports/Case Series||Actionable||In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK initially responded to Xalkori (crizotinib), but then progressed due to acquisition of the secondary resistance mutation, ALK F1174V, and then responded to treatment with Alecensa (alectinib), demonstrating a complete response in one lung nodule and a 44% decrease in size in a second lung nodule (PMID: 26464158).||26464158|