Skip Navigation LinksHome > March 2014 - Volume 9 - Issue 3 > HIP1–ALK, A Novel ALK Fusion Variant that Responds to Crizot...
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000087
Original Articles

HIP1–ALK, A Novel ALK Fusion Variant that Responds to Crizotinib

Fang, Douglas D. PhD*; Zhang, Bin PhD*; Gu, Qingyang PhD*; Lira, Maruja BS; Xu, Qiang PhD; Sun, Hongye PhD; Qian, Maoxiang PhD; Sheng, Weiqi MD, PhD§; Ozeck, Mark BS; Wang, Zhenxiong PhD; Zhang, Cathy MS; Chen, Xinsheng MS*; Chen, Kevin X. PhD*; Li, Jian PhD*; Chen, Shu-Hui PhD*; Christensen, James PhD; Mao, Mao MD, PhD; Chan, Chi-Chung PhD*

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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.

Copyright © 2014 by the International Association for the Study of Lung Cancer

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