Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation.
Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation.
复制标题
用MEHD7945A对EGFR和HER3的双重靶向克服了对EGFR抑制剂和辐射的抗性。
DOI：
10.1158/0008-5472.can-12-1611
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Harari PM
中科院分区：
文献类型：
--
作者：
Huang S;Li C;Armstrong EA;Peet CR;Saker J;Amler LC;Sliwkowski MX;Harari PM
EGFR inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A when compared to cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Further, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor-resistant cells by modulating cell cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof of concept that MEHD7945A can effectively overcome EGFR inhibitor resistance.
