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Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor
Zexi Hu1,2, Yong Hu1,2, Xicheng Liu2
1College of Life Sciences, Beijing Normal University, Beijing, China.
Abstract:
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.
Insights
The HER2H878Y mutation drives lung adenocarcinoma in vivo and depends on continuous expression for tumor maintenance. Targeting this mutation with HKI-272 and rapamycin shows therapeutic promise.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- HER2 is a key oncogenic target within the EGFR family.
- HER2 mutations, unlike EGFR, are rarely found in the kinase domain's activation loop.
- The HER2H878Y mutation's in vivo tumorigenicity and therapeutic strategies were previously undetermined.
Purpose of the Study:
- To investigate the in vivo tumorigenicity of the HER2H878Y mutation in lung adenocarcinoma.
- To explore therapeutic interventions for HER2H878Y-driven lung tumors.
- To assess the efficacy of tyrosine kinase inhibitors and combination therapies.
Main Methods:
- Development of a lung adenocarcinoma transgenic mouse model with inducible HER2H878Y expression.
- Analysis of tumor formation, differentiation, and dependence on HER2H878Y.
- Evaluation of downstream signaling pathway activation (PLCγ1, STAT5, AKT).
- Assessment of therapeutic responses to HKI-272 (tyrosine kinase inhibitor) and Rapamycin (mTOR inhibitor).
Main Results:
- HER2H878Y expression induced poorly differentiated lung adenocarcinoma with BAC features in vivo.
- Tumor growth was dependent on sustained HER2H878Y expression.
- Hyperactivation of HER2 downstream signaling mediators was observed.
- HKI-272 treatment led to significant tumor shrinkage.
- Combination therapy with HKI-272 and Rapamycin demonstrated superior cytotoxicity and enhanced apoptosis.
Conclusions:
- The HER2H878Y mutant is tumorigenic in vivo and represents a viable drug target.
- Continuous HER2H878Y expression is crucial for maintaining tumor growth.
- Targeting HER2H878Y with HKI-272 and rapamycin warrants clinical trial assessment.
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