HIP1-ALK, a novel ALK fusion variant that responds to crizotinib

J Thorac Oncol. 2014 Mar;9(3):285-94. doi: 10.1097/JTO.0000000000000087.

Abstract

Introduction: The aim of this study was to identify anaplastic lymphoma kinase (ALK) rearrangements in lung cancer patient-derived xenograft (PDX) models and to explore their responses to crizotinib.

Methods: Screening of 99 lung cancer PDX models by the NanoString ALK fusion assay identified two ALK-rearranged non-small-cell lung cancer (NSCLC) tumors, including one harboring a previously known echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion and another containing an unknown ALK fusion variant. Expression array, RNA-Seq, reverse transcription polymerase chain reaction, and direct sequencing were then conducted to confirm the rearrangements and to identify the novel fusion partner in the xenograft and/or the primary patient tumor. Finally, pharmacological studies were performed in PDX models to evaluate their responses to ALK inhibitor crizotinib.

Results: Two ALK-rearranged NSCLC PDX models were identified: one carried a well-known EML4-ALK variant 3a/b and the other harbored a novel huntingtin interacting protein 1 (HIP1)-ALK fusion gene. Exon 28 of the HIP1 gene located on chromosome 7 was fused to exon 20 of the ALK gene located on chromosome 2. Both cases were clinically diagnosed as squamous cell carcinoma. Compared with the other lung cancer PDX models, both ALK-rearranged models displayed elevated ALK mRNA expression. Furthermore, in vivo efficacy studies demonstrated that, similar to the EML4-ALK-positive model, the HIP1-ALK-containing PDX model was sensitive to treatment with crizotinib.

Conclusions: Discovery of HIP1 as a fusion partner of ALK in NSCLC is a novel finding. In addition, the HIP1-ALK-rearranged tumor is sensitive to treatment with crizotinib in vivo, implicating HIP1-ALKas an oncogenic driver of lung tumorigenesis. Collectively, our results indicate that HIP1-ALK-positive NSCLC may benefit from clinical applications of crizotinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Crizotinib
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • Female
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Oncogene Proteins, Fusion / antagonists & inhibitors
  • Oncogene Proteins, Fusion / genetics*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • HIP1 protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • RNA, Messenger
  • Crizotinib
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases