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|Ref Type||Journal Article|
|Authors||Ou SH, Klempner SJ, Greenbowe JR, Azada M, Schrock AB, Ali SM, Ross JS, Stephens PJ, Miller VA|
|Title||Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib.|
|Journal||Journal of thoracic oncology : official publication of the International|
|Abstract Text||Huntingtin-interacting protein 1 (HIP1) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC). To date, two variants of HIP1-ALK (H21; A20) and (H28; A20) have been identified in NSCLC. However, the response of patients with NSCLC harboring HIP1-ALK to ALK inhibitors and potential resistance mechanisms to such remain unknown. Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively) located in the hydrophobic regulatory spine (R-spine) of the ALK kinase in both the cases as identified by a comprehensive next-generation sequencing-based assay performed on biopsies of new liver metastases that developed during alectinib treatment.|
|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||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||lung non-small cell carcinoma||predicted - resistant||Alectinib||Case Reports/Case Series||Actionable||In a clinical case study, a patient with EML4-ALK positive non-small cell lung cancer initially responded to Alecensa (alectinib), but progressed with the emergence of a secondary ALK I1171S mutation (PMID: 25393796).||25393796|