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 PLCĪ³1, 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.