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- Title
Sensitization of Resistant Cells with a BET Bromodomain Inhibitor in a Cell Culture Model of Deep Intrinsic Resistance in Breast Cancer.
- Authors
Singh, Balraj; Sarli, Vanessa N.; Milligan, Ryan D.; Kinne, Hannah E.; Shamsnia, Anna; Washburn, Laura J.; Addanki, Sridevi; Lucci, Anthony
- Abstract
Simple Summary: Cell culture models of cancer typically favor proliferative but therapy-sensitive cells because body-like selection pressures are absent. To address this limitation, we previously described a function-based selection strategy to model deep intrinsic resistance in cultures of triple-negative breast cancer cells. Our methods were designed to reveal therapy-resistant, adaptable cancer cells that opportunistically switch between quiescence and proliferation. To determine the validity of this approach in identifying noncytotoxic drugs that could inhibit highly resistant breast cancer cells, we used our novel cell culture model to evaluate a well-known BET bromodomain inhibitor, JQ1, which modulates the cancer epigenome. JQ1 has been found to inhibit resistant cancer cells in several cancer types, including breast cancer. Low-dose JQ1 inhibited the growth of highly adaptable/resistant breast cancer cells in our cell culture model. Our results support the validity of a cell culture-based approach for modeling cancer. We treated highly metabolically adaptable (SUM149-MA) triple-negative inflammatory breast cancer cells and their control parental SUM149-Luc cell line with JQ1 for long periods to determine its efficacy at inhibiting therapy-resistant cells. After 20 days of treatment with 1–2 µM of JQ1, which killed majority of cells in the parental cell line, a large number of SUM149-MA cells survived, consistent with their pan-resistant nature. Interestingly, though, the JQ1 treatment sensitized resistant cancer cells in both the SUM149-MA and SUM149-Luc cell lines to subsequent treatment with doxorubicin and paclitaxel. To measure JQ1-mediated sensitization of resistant cancer cells, we first eradicated approximately 99% of relatively chemotherapy-sensitive cancer cells in culture dishes by long treatments with doxorubicin or paclitaxel, and then analyzed the remaining resistant cells for survival and growth into colonies. In addition, combination, rather than sequential, treatment with JQ1 and doxorubicin was also effective in overcoming resistance. Notably, Western blotting showed that JQ1-treated cancer cells had significantly lower levels of PD-L1 protein than did untreated cells, indicating that JQ1 treatment may reduce tumor-mediated immune suppression and improve the response to immunotherapy targeting PD-L1. Finally, JQ1 treatment with a low 62.5 nM dose sensitized another resistant cell line, FC-IBC02-MA, to treatment with doxorubicin and paclitaxel.
- Subjects
BREAST tumor diagnosis; THERAPEUTIC use of antineoplastic agents; BROMODOMAIN-containing proteins; CELL culture; INFLAMMATION; CARCINOGENESIS; WESTERN immunoblotting; DOXORUBICIN; RH isoimmunization; CANCER relapse; METASTASIS; CELL receptors; RESEARCH funding; BREAST tumors; DRUG resistance in cancer cells; EPIGENOMICS; IMMUNOTHERAPY; CHEMICAL inhibitors
- Publication
Cancers, 2023, Vol 15, Issue 7, p2036
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers15072036