Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor
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Zexi Hu1,2,*, Yong Hu1,2,*, Xicheng Liu2, Rongwen Xi2, Aiqun Zhang3, Deruo Liu4, Qiang Xie5 and Liang Chen2,6
1 College of Life Sciences, Beijing Normal University, Beijing, China
2 National Institute of Biological Sciences, Beijing, China
3 The General Hospital of People’s Liberation Army (301 hospital), Beijing, China
4 Department of thoracic surgery, China-Japan Friendship Hospital, Beijing, China
5 Fuzhou Pulmonary Hospital of Fujian, Fujian, China
6 National Institute of Biological Sciences, Collaborative Innovation Center for Cancer Medicine, Beijing, China
* Co-first author
Liang Chen, email:
Keywords: HER2, H878Y, Transgenic mouse model, targeting therapy, combinational therapy
Received: May 13, 2015 Accepted: August 08, 2015 Published: September 08, 2015
HER2, a well established oncogenic member of EGFR family, is among the most intensely investigated kinase drug targets. In contrast to hotspot mutations of EGFR, few mutations of HER2 locate in activation loop within kinase domain. We previously reported the molecular mechanism underlying hyper kinase activity of HER2H878Y, a mutation located in activation loop. However, its tumorigenicity in vivo and relevant therapeutics remain to be determined. Here, we report for the first time that HER2H878Y was tumorigenic in vivo in lung adenocarcinoma transgenic mouse model. Induced expression of HER2H878Y in lung epithelial compartments resulted in formation of poorly differentiated lung adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. Strikingly, we found that these tumors depended on continuous expression of HER2H878Y for maintenance. Typical HER2 downstream signaling mediators, including PLCγ1, STAT5 and AKT, were hyperactivated in HER2H878Y driven lung tumors. More importantly, administration of HKI-272, a tyrosine kinase inhibitor (TKI), efficiently shrank HER2H878Y driven tumors in transgenic mouse model. Moreover, we found that combinational treatment with HKI272 and mTOR inhibitor, Rapamycin, showed a superior cytotoxicity to H878Y mutant transformed cells and enhanced activity to elicit apoptosis and inhibit growth in situ in tumorous area. Our work therefore showed that HER2H878Y mutant was a reasonable drug target. Hence, our work supported the assessment of HKI-272/rapamycin treatment in clinical trials.
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