التفاصيل البيبلوغرافية
| العنوان: |
Ribociclib Induces Broad Chemotherapy Resistance and EGFR Dependency in ESR1 Wildtype and Mutant Breast Cancer. |
| المؤلفون: |
Mayayo-Peralta, Isabel, Faggion, Beatrice, Hoekman, Liesbeth, Morris, Ben, Lieftink, Cor, Goldsbrough, Isabella, Buluwela, Lakjaya, Siefert, Joseph C., Post, Harm, Altelaar, Maarten, Beijersbergen, Roderick, Ali, Simak, Zwart, Wilbert, Prekovic, Stefan |
| المصدر: |
Cancers; Dec2021, Vol. 13 Issue 24, p6314-6314, 1p |
| مصطلحات موضوعية: |
DISEASE progression, GENETIC mutation, DRUG tolerance, EPIDERMAL growth factor receptors, PROTEIN kinase inhibitors, ANTINEOPLASTIC agents, ESTROGEN receptors, CELL lines, BREAST tumors, DRUG resistance in cancer cells |
| مستخلص: |
Simple Summary: Disease progression while receiving treatment is a major problem in breast cancer. Mutations in the oestrogen receptor-α often lead to loss of drug activity, resulting in an inability of anti-oestrogens to stop cancer growth. There is an urgent need to establish which therapies can effectively eradicate cancer cells and also to understand how these therapies work. The aim of this study was to find compounds that diminish viability of breast cancer cells harbouring mutated oestrogen receptor-α. We discovered that cells, regardless of their oestrogen receptor-α mutational status, are vulnerable to the cell-cycle inhibitor ribociclib, which causes senescence accompanied by a decrease in sensitivity to various chemotherapies. Importantly, we found that viability of ribociclib-induced senescent cells is maintained by the EGFR signalling pathway, which may be therapeutically exploited. While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15–40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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