Yan Si1, Xinxin Pei1, Xiangfang Wang1, Qianqian Han1, Changzhi Xu1, Buchang Zhang1.
Abstract
BACKGROUND: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a recurrent phenomenon during clinical therapy of non-small-cell lung cancer (NSCLC). Studies have shown that HER2 is a key factor contributing to drug resistance in a variety of cancers. Furthermore, we have observed that HER2 is overexpressed in PC-9 NSCLC cells with acquired gefitinib-resistance (PC-9/GR) as compared to that in PC-9 cells.
OBJECTIVE: We hypothesized that blocking both EGFR and HER2 may serve as a potential strategy for the treatment of NSCLC with acquired gefitinib-resistance.
METHODS: To target both EGFR and HER2 simultaneously, we developed a bispecific antibody HECrossMAb, which was derived from a humanized Cetuximab and Trastuzumab. The binding affinity of HECrossMAb for EGFR and HER2 was measured using an enzyme-linked immunosorbent assay. The MTT assay was used to determine the effect of HECrossMAb on the proliferation of PC-9 and PC-9/GR cells in vitro. Finally, the effect of HECrossMAb on PI3K/AKT signaling and associated transcription factors was measured using western blot analysis.
RESULTS: Our results showed that HECrossMAb exerts enhanced cytotoxicity in both PC-9 and PC-9/GR cells by inhibiting the activation of PI3K/AKT signaling and expression of relevant transcription factors such as AEG-1, c-Myc, and c-Fos.
CONCLUSION: Our results suggest that HECrossMAb may function as a potential therapeutic agent for treating NSCLC overexpressing EGFR and HER2. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
BACKGROUND: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a recurrent phenomenon during clinical therapy of non-small-cell lung cancer (NSCLC). Studies have shown that HER2 is a key factor contributing to drug resistance in a variety of cancers. Furthermore, we have observed that HER2 is overexpressed in PC-9 NSCLC cells with acquired gefitinib-resistance (PC-9/GR) as compared to that in PC-9 cells.
OBJECTIVE: We hypothesized that blocking both EGFR and HER2 may serve as a potential strategy for the treatment of NSCLC with acquired gefitinib-resistance.
METHODS: To target both EGFR and HER2 simultaneously, we developed a bispecific antibody HECrossMAb, which was derived from a humanized Cetuximab and Trastuzumab. The binding affinity of HECrossMAb for EGFR and HER2 was measured using an enzyme-linked immunosorbent assay. The MTT assay was used to determine the effect of HECrossMAb on the proliferation of PC-9 and PC-9/GR cells in vitro. Finally, the effect of HECrossMAb on PI3K/AKT signaling and associated transcription factors was measured using western blot analysis.
RESULTS: Our results showed that HECrossMAb exerts enhanced cytotoxicity in both PC-9 and PC-9/GR cells by inhibiting the activation of PI3K/AKT signaling and expression of relevant transcription factors such as AEG-1, c-Myc, and c-Fos.
CONCLUSION: Our results suggest that HECrossMAb may function as a potential therapeutic agent for treating NSCLC overexpressing EGFR and HER2. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Entities:
Keywords:
EGFR; HE<sub>CrossMAb</sub>.; HER2; NSCLC; acquired gefitinib-resistance; bispecific antibody
Mesh：
Substances：
Year: 2021
PMID： 34602035 DOI： 10.2174/0929866528666210930170624
Source DB: PubMed Journal: Protein Pept Lett ISSN： 0929-8665 Impact factor: 1.890