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Afatinib Against Esophageal Or Head-And-Neck Squamous Cell

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Afatinib Against Esophageal Or Head-And-Neck Squamous Cell Published OnlineFirst May 20, 2016; DOI: 10.1158/1535-7163.MCT-15-0737 Companion Diagnostics and Cancer Biomarkers Molecular Cancer Therapeutics Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC Yu Nakamura1,2, Yosuke Togashi1, Hirokazu Nakahara3,4, Shuta Tomida1, Eri Banno1, Masato Terashima1, Hidetoshi Hayashi5, Marco A. de Velasco1, Kazuko Sakai1, Yoshihiko Fujita1, Takatsugu Okegawa2, Kikuo Nutahara2, Suguru Hamada3, and Kazuto Nishio1 Abstract The prognosis for patients with advanced esophageal or line, and the mutation had a transforming potential and head-and-neck squamous cell carcinoma (ESCC or HNSCC) exhibited tumorigenicity in an NIH3T3 cell line, indicating remains poor, and the identification of additional oncogenes that this HER4 mutation was an activating oncogenic muta- and their inhibitors is needed.Inthisstudy,weevaluated tion. Afatinib dramatically reduced the phosphorylation level the sensitivities of several ESCC and HNSCC cell lines to HER of EGFR or HER4 and induced apoptosis in the two cell lines. inhibitors (cetuximab, erlotinib, and afatinib) in vitro and In vivo, tumor growth was also dramatically decreased by found two cell lines that were hypersensitive to afatinib. afatinib. In a database, the frequencies of HER family gene Sequence analyses for the afatinib-targeted HER family genes mutations in ESCC or HNSCC ranged from 0% to 5%. In in the two cell lines revealed that one cell line had a previously particular, HER4 mutations have been found relatively fre- reported activating EGFR L861Q mutation, whereas the other quentlyinHNSCC.Consideringtheaddictionofcancer had an HER4 G1109C mutation of unknown function. No cells to activating oncogenic EGFR or HER4 mutations amplification of HER family genes was found in either of the for proliferation, HNSCC or ESCC with such oncogenic muta- two cell lines. The phosphorylation level of HER4 was elevated tions might be suitable for targeted therapy with afatinib. in the HER4 G1109C mutation-overexpressed HEK293 cell Mol Cancer Ther; 15(8); 1–10. Ó2016 AACR. Introduction Despite improvements in surgical techniques, chemotherapy, and radiotherapy, the prognosis of ESCC and HNSCC remains Esophageal squamous cell carcinoma (ESCC) and head-and- very poor. Although recent breakthroughs in molecular biology neck squamous cell carcinoma (HNSCC) are included among have assisted in translational research, giving hope for individ- the most aggressive cancers. Because of the risk factors com- ualized therapy and better disease management, the inhibition monly associated with the development of ESCC and HNSCC, of EGFR using cetuximab is, to date, the approved targeted several studies have revealed that ESCC and HNSCC have approach for improving survival in patients with HNSCC similar molecular alterations (1–8). For instance, cyclin D1, (9–11). Therefore, further understanding of the molecular p53, EGFR, and c-myc are common important genetic altera- biology of ESCC and HNSCC is needed, and the identification tions in ESCC and HNSCC carcinogenesis. In addition, it is of oncogenes with effects similar to those of EGFR mutations or common to see synchronous and metachronous tumors devel- anaplastic lymphoma kinase gene (ALK) rearrangements and op in this region, and the concept of "field cancerization" has upon which cancer cells are dependent is needed (12). become widely accepted (5, 6). The HER-family of receptor tyrosine kinases consists of four members: EGFR (HER1), HER2, HER3, and HER4. The HER 1Department of Genome Biology, Kindai University Faculty of Medi- molecule structure has three regions, an extracellular ligand–bind- cine, Osaka, Japan. 2Department of Urology, Kyorin University School 3 ing region, and intracellular region with tyrosine kinase activity, of Medicine, Tokyo, Japan. Department of Oral and Maxillofacial – Surgery, Kindai University Faculty of Medicine, Osaka, Japan. 4Depart- and a transmembrane region (13). HER family related signals are ment of Oral and Maxillofacial Surgery, Graduate School of Medicine, reported to play an important role in modulating cell prolife- 5 Osaka City University, Osaka, Japan. Department of Medical Oncol- ration, survival, migration, and differentiation. HER family over- ogy, Kindai University Faculty of Medicine, Osaka, Japan. expression has been identified in a variety of human cancers Note: Supplementary data for this article are available at Molecular Cancer including ESCC and HNSCC (14–16). Afatinib, an irreversible Therapeutics Online (http://mct.aacrjournals.org/). HER-family blocker (17, 18), has a remarkable antitumor effect Corresponding Author: Kazuto Nishio, Kindai University Faculty of Medicine, against EGFR-mutated non–small cell lung cancer (NSCLC; 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone: 81-72-366- refs. 19, 20). In addition, a recent phase III study showed the 0221; Fax: 81-72-367-6369; E-mail: [email protected] efficacy of afatinib in patients with recurrent or metastatic HNSCC doi: 10.1158/1535-7163.MCT-15-0737 after the failure of platinum-based therapy (21), and in a phase I Ó2016 American Association for Cancer Research. study, one of 7 patients with esophageal cancer achieved a www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 20, 2016; DOI: 10.1158/1535-7163.MCT-15-0737 Nakamura et al. partial response with afatinib (22). In the present study, we tested 7900HT Sequence Detection System (Applied Biosystems), and the effects of HER inhibitors, including afatinib, in several ESCC the results were analyzed using CopyCaller software version 2.0 and HNSCC cell lines in vitro and found two cell lines that were (Applied Biosystems). The experiment was performed in hypersensitive; one of these cell lines had an HER4 mutation with triplicate. an unknown function. Consequently, the role of this muta- tion was investigated and a xenograft study using afatinib was Plasmid construction and transfectants performed. A pRetro-IRES-ZsGreen1 vector including a full-length cDNA fragment encoding human HER4 was purchased from Clonetech. Materials and Methods The HER4 point mutations were amplified using the PrimeSTAR Mutagenesis Basal Kit (TaKaRa). Viral production was performed Cell cultures and reagents as previously described (27). The viral vectors and stable viral The HEK293 (human embryonic kidney cell line), NIH3T3 transfectant cell lines were designated as pRetro-EGFP, pRetro- (mouse fibroblast cell line), human HNSCC cell lines, KYSE30, HER4 WT, pRetro-HER4 G1109C, pRetro-HER4 E317K, HEK293/ and KYSE50 (human ESCC cell lines) cell lines were maintained EGFP, HEK293/HER4 WT, HEK293/HER4 G1109C, HEK293/ in DMEM with 10% FBS were maintained in DMEM medium HER4 E317K, NIH3T3/EGFP, NIH3T3/HER4 WT, NIH3T3/HER4 (Sigma-Aldrich) supplemented with 10% FBS (GIBCO BRL) in a G1109C, and NIH3T3/HER4 E317K, respectively. humidified atmosphere of 5% CO2 at 37 C. The KYSE170, KYSE180, and KYSE270 cell lines were maintained in a 1:1 mixture of Ham F12 medium (Sigma-Aldrich) and RPMI- Antibodies 1640 medium (Sigma-Aldrich) supplemented with 2% FBS in Rabbit antibodies specific for EGFR, phospho-EGFR, HER2, ahumidified atmosphere of 5% CO2 at 37 C. The KYSE70 cell phospho-HER2, HER3, phospho-HER3, HER4, phospho-HER4, line was maintained in DMEM with 2% FBS in a humidified AKT, phospho-AKT, ERK1/2, phospho-ERK1/2, poly (ADP- atmosphere of 5% CO2 at 37 C. The KYSE150 cell line was ribose) polymerase (PARP), caspase-3, cleaved PARP, cleaved maintained in Ham F12 with 2% FBS in a humidified atmo- caspase-3, and b-actin were obtained from Cell Signaling sphere of 5% CO2 at 37 C. The HEK293 and NIH3T3 cell lines Technology. were obtained from the ATCC in 2006. The human ESCC cell lines were established in Kyoto University (23–25), and Western blot analysis obtained from Japanese Collection of Research Bioresources in A western blot analysis was performed as described previ- 2011. The HNSCC cell lines were also obtained from Japanese ously (26). Briefly, subconfluent cells were washed with cold Collection of Research Bioresources in 2012. The HEK293, phosphate-buffered saline (PBS) and harvested with Lysis A KYSE50, KYSE270, SAS, and OSC-19 cell lines were analyzed buffer containing 1% Triton X-100, 20 mmol/L Tris-HCl using a short tandem repeat (STR) method in August 2015, and (pH7.0), 5 mmol/L EDTA, 50 mmol/L sodium chloride, 10 the HEK293, KYSE50, KYSE270, SAS, and OSC-19 cell lines were mmol/L sodium pyrophosphate, 50 mmol/L sodium fluoride, authenticated. Erlotinib and afatinib were purchased from Sell- 1 mmol/L sodium orthovanadate, and a protease inhibitor mix, eck Chemicals, and cetuximab was purchased from ImClone Complete (Roche Diagnostics). Whole-cell lyses were separated Systems Incorporated. NRG1, an HER4 ligand, was purchased using SDS-PAGE and were blotted onto a polyvinylidene fluo- from R&D Systems. ride membrane. After blocking with 3% BSA in a TBS buffer (pH 8.0) with 0.1% Tween-20, the membrane was probed with the Cellular growth and growth inhibition assay in vitro primary antibody. After rinsing twice with TBS buffer, the The cellular growth and growth-inhibitory effects of the drugs membrane was incubated with a horseradish peroxidase–con- or siRNA were examined using a 3, 4, 5-dimethyl-2H-tetrazolium jugated secondary antibody and washed, followed by visuali- bromide assay (MTT; Sigma-Aldrich),
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