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

Sai-Hong Ignatius Ou; Samuel J Klempner; Joel R Greenbowe; Michele Azada; Alexa B Schrock; Siraj M Ali; Jeffrey S Ross; Philip J Stephens; Vincent A Miller

doi:10.1097/JTO.0000000000000368

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

J Thorac Oncol. 2014 Dec;9(12):1821-5. doi: 10.1097/JTO.0000000000000368.

Authors

Sai-Hong Ignatius Ou¹, Samuel J Klempner, Joel R Greenbowe, Michele Azada, Alexa B Schrock, Siraj M Ali, Jeffrey S Ross, Philip J Stephens, Vincent A Miller

Affiliation

¹ *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.

PMID: 25393796
DOI: 10.1097/JTO.0000000000000368

Abstract

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Anaplastic Lymphoma Kinase
Carbazoles / therapeutic use*
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Crizotinib
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Disease Progression
Drug Resistance, Neoplasm / genetics
Female
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Middle Aged
Mutation*
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Piperidines / therapeutic use*
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / therapeutic use
Pyridines / therapeutic use
Receptor Protein-Tyrosine Kinases / genetics*
Receptor Protein-Tyrosine Kinases / metabolism

Substances

Carbazoles
DNA-Binding Proteins
HIP1 protein, human
Oncogene Proteins, Fusion
Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Crizotinib
ALK protein, human
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
alectinib