EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency
| Autor: | Shi Hu, Ying Tang, Yue Yu, Wenyan Fu, Xuting Ye, Min Ding, Shuowu Liu, Yongji Yang, Fangxing Lin, Xiaoyan Fan, Changhai Lei, Tian Li, Yafeng Shen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Indazoles Cell Notch signaling pathway Mice Nude Apoptosis Triple Negative Breast Neoplasms Mice SCID Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Cancer stem cell Antibodies Bispecific Antineoplastic Combined Chemotherapy Protocols Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Tarextumab PI3K/AKT/mTOR pathway Cell Proliferation EGFR inhibitors Mice Inbred BALB C Sulfonamides Receptors Notch Cell growth business.industry Prognosis Xenograft Model Antitumor Assays ErbB Receptors Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Neoplastic Stem Cells Cancer research Signal transduction business Proto-Oncogene Proteins c-akt |
| Zdroj: | Clinical Cancer Research. 25:2835-2847 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Both EGFR and PI3K-Akt signaling pathways have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signaling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signaling. Experimental Design: We utilized cell-based models to study Notch signaling in drug-induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumors were used to evaluate the antitumor effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that EGFR/Notch targeting bispecific antibodies exhibited a notable antistem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in triple-negative breast cancer cell line–based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumor effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumors. Mechanistically, bispecific antibody treatment inhibits the stem cell–like subpopulation, reduces tumor-initiating cell frequency, and downregulates the mesenchymal gene expression. Conclusions: These findings suggest that the coblockade of EGFR and Notch signaling has the potential to increase the response to PI3K inhibition, and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment. |
| Databáze: | OpenAIRE |
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