Combination of fulvestrant and chemotherapy in ESR1 Y537S mutant breast cancer cells and potential synergy mechanism related to p53 wildtype
| Autor: | Ma Wen, Nanlin Li, C. Guarducci, Avery S. Feit, Rinath Jeseslsohn, Gabriella Cohen, Francisco Hermida-Prado, Hongliang Wei, Myles Brown, Wenting Pan, Agostina Nardone |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 38:1065-1065 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2020.38.15_suppl.1065 |
| Popis: | 1065 Background: The acquisition of ligand-independent ESR1 mutations during endocrine therapy in metastatic ER+ breast cancer is a common mechanism of resistance to endocrine treatment, particularly aromatase inhibitors, and found in more than 30% of patients with metastatic ER+ breast cancer. Our recent work showed that the ER mutations confer resistance to currently available endocrine treatments while promoting an aberrant ER transcriptional activity that drives metastases. These results underscore the importance of targeting the ESR1 mutations even after the development of endocrine resistance. We hypothesized that during chemotherapy treatment, the ESR1 mutations remain an important driver of tumor growth and metastases and therefore drugs targeting the ESR1 mutation could enhance the efficacy of chemotherapy. In this study we investigated the combination of chemotherapy with the selective estrogen receptor degrader in the presence of WT and mutant ER. Methods: We performed synergy studies testing the combination of fulvestrant with chemotherapy treatments commonly used in ER+ metastatic breast cancer including 5FU (representing capecitabine), adriamycin and paclitaxel using MCF7 and T47D breast cancer cell lines engineered to express doxycycline inducible Y537S-ESR1 mutation. Results: We found that in MCF7 cells the combination of chemotherapy and fulvestrant was synergistic and the synergy was augmented with the induction of the Y537S mutation. In contrast, there was no synergy in T47D cells that harbor a P53 mutation. We confirmed that the synergistic activity of fulvestrant with chemotherapy is dependent on P53 by generating P53 knock-out MCF7 cells using CRISPR-cas9. Additionally, cell cycle and apoptosis analyses showed that the synergistic activity was mainly due to increased effects on G1 arrest rather than apoptosis. Conclusions: Our study indicates that chemotherapy and fulvestrant are synergistic in ER+ breast cancer and the synergy is increased in the presence of the Y537S ESR1 mutation and is dependent on P53 activity. These results support a clinical trial testing the addition of fulvestrant or other novel selective estrogen receptor degraders in patients with metastatic ER+ breast cancer who are starting chemotherapy treatment. |
| Databáze: | OpenAIRE |
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