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

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HIP1–ALK, A Novel ALK Fusion Variant that Responds to Crizotinib Douglas D. Fang, PhD, Bin Zhang, PhD, Qingyang Gu, PhD, Maruja Lira, BS, Qiang Xu, PhD, Hongye Sun, PhD, Maoxiang Qian, PhD, Weiqi Sheng, MD, PhD, Mark Ozeck, BS, Zhenxiong Wang, PhD, Cathy Zhang, MS, Xinsheng Chen, MS, Kevin X. Chen, PhD, Jian Li, PhD, Shu-Hui Chen, PhD, James Christensen, PhD, Mao Mao, MD, PhD, Chi-Chung Chan, PhD Journal of Thoracic Oncology Volume 9, Issue 3, Pages 285-294 (March 2014) DOI: 10.1097/JTO.0000000000000087 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Detection of ALK rearrangements and overexpression of the ALK gene in two NSCLC PDX models. A, Quantification of ALK 5′ and 3′ expression levels using the NanoString ALK fusion assay. B, ALK 3′ overexpression in both models as measured by ALK 3′/5′ score in the fusion assay. A background threshold of twofold was denoted by a horizontal dash line (B). C, ALK exon 20 reporter counts detected in NanoString assay. A background threshold of 60 reporter counts was denoted by a horizontal dash line (B). D, Expression levels of ALK in NSCLC PDX models determined by a GeneChip PrimeView human gene expression array or a GeneChip Human Genome U133 Plus 2.0 array in a panel of 22 and seven models, respectively. ALK, anaplastic lymphoma kinase; PDX, patient–derived xenograft; NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2014 9, 285-294DOI: (10.1097/JTO.0000000000000087) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Identification of a novel HIP1–ALK fusion by RNA-Seq. A, Circos plots depicting ALK rearrangements in LU-01-0015 and LU-01-0319. Chromosomes were drawn to scale around the rim of the circle, and data are plotted on these coordinates. The blue arc and red arc represent intrachromosomal and interchromosomal translocation, respectively. B, Representative aligned reads were shown to map across the exon–exon fusion junction between HIP1 or EML4 and exon 20 of ALK in LU-01-0015 and LU-01-0319, respectively, as illustrated in the schematic diagram. In LU-01-0319, the split-reads are shown aligning on the breakpoints of EML4–ALK variant 3a (A) and 3b (B). ALK, anaplastic lymphoma kinase; HIP1, huntingtin interacting protein 1; EML4, echinoderm microtubule-associated protein-like 4. Journal of Thoracic Oncology 2014 9, 285-294DOI: (10.1097/JTO.0000000000000087) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Validation of ALK rearrangements by RT-PCR and direct sequencing. A, RT-PCR products corresponding to HIP1–ALK and EML4–ALK fusion genes, respectively, in both the primary patient (PA) and PDX tissues. M, DNA ladder. B, Direct sequencing of cDNA revealed fusion junctions of HIP1–ALK and EML4–ALK translocations in LU-01-0015 and LU-01-0319, respectively. The corresponding locations of the genes were indicated by color-coded bars. C, Schematic representation of HIP1–ALK protein. Regions corresponding to HIP1 and ALK were shown in blue and red, respectively. The fusion protein joins the tyrosine kinase domain of ALK to the TH domain of HIP1. RT-PCR, reverse transcription polymerase chain reaction; ALK, anaplastic lymphoma kinase; HIP1, huntingtin interacting protein 1; EML4, echinoderm microtubule-associated protein-like 4; PA, primary patient; PDX, patient-derived xenograft; TH, talin homology. Journal of Thoracic Oncology 2014 9, 285-294DOI: (10.1097/JTO.0000000000000087) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 The histology of ALK-rearranged NSCLC patient (PA) and serially passaged PDX tumors and the growth curves of corresponding PDX tumors. The growth characteristics were summarized in the tables on the left. T250 and T500: the number of days required for a tumor to reach 250 mm3 and 500 mm3, respectively. T500-T250: the number of days required for a tumor to grow from 250 mm3 to 500 mm3. PDX, patient-derived xenograft; ALK, anaplastic lymphoma kinase; HIP1, huntingtin interacting protein 1; EML4, echinoderm microtubule-associated protein-like 4; NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2014 9, 285-294DOI: (10.1097/JTO.0000000000000087) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Antitumor activity of crizotinib in ALK wild-type, and HIP1–ALK- and EML4–ALK-rearranged NSCLC PDX models. Crizotinib (by mouth, daily) or cisplatin (by intraperitoneal every week) were administered in tumor-bearing mice for 3 weeks (n=6 or 7 in each group). Data were shown as mean ± standard error of the mean. In both ALK-rearranged models the average tumor volumes in the crizotinib- or cisplatin-treated groups at the endpoint are significantly less than the vehicle control group as determined using one-way analysis of variance. *p < 0.005, **p< 0.01, **p< 0.001. ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; HIP1, huntingtin interacting protein 1; PDX, patient-derived xenograft; NSCLC, non–small-cell lung cancer; WT, wild type. Journal of Thoracic Oncology 2014 9, 285-294DOI: (10.1097/JTO.0000000000000087) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions