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.
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.
*Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California; †Foundation Medicine, Inc., Cambridge, Massachusetts; and ‡Departmente of Pathology and Laboratory Medicine, Albany Medical Center, Albany, New York.
Sai-Hong Ignatius
SH
Ou
Samuel J
SJ
Klempner
Joel R
JR
Greenbowe
Michele
M
Azada
Alexa B
AB
Schrock
Siraj M
SM
Ali
Jeffrey S
JS
Ross
Philip J
PJ
Stephens
Vincent A
VA
Miller
D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077547:Crizotinib; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
D002227:Carbazoles; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib