MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib

Young, AI; Law, AM; Castillo, L; Chong, S; Cullen, HD; Koehler, M; Herzog, S; Brummer, T; Lee, EF; Fairlie, WD; Lucas, MC; Herrmann, D; Allam, A; Timpson, P; Watkins, DN; Millar, EK; O&#39;Toole, SA; Gallego-Ortega, D; Ormandy, CJ; Oakes, SR

Author(s): Young, AI; Law, AM; Castillo, L; Chong, S; Cullen, HD; Koehler, M; Herzog, S; Brummer, T; Lee, EF; Fairlie, WD; Lucas, MC; Herrmann, D; Allam, A; Timpson, P; Watkins, DN; Millar, EK; O'Toole, SA; Gallego-Ortega, D; Ormandy, CJ; Oakes, SR;
Details: Publication Year 2016-12-08,Volume 18,Issue #1,Page 125
Journal Title: Breast Cancer Research
Publication Type: Journal Article
Abstract: BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.
Publisher: BioMed Central
Research Division(s): Structural Biology
PubMed ID: 27931239
Publisher's Version: https://doi.org/10.1186/s13058-016-0781-6
Open Access at Publisher's Site: https://doi.org/10.1186/s13058-016-0781-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-05-26 03:48:58

Last Modified: 2020-04-07 02:17:48