MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Young, Adelaide I. J.; Law, Andrew; Castillo, Lesley; Chong, Sabrina; Cullen, Hayley; Koehler, Martin; Herzog, Sebastian; Brummer, Tilman; Lee, Erinna; Fairlie, Walter; Lucas, Morghan; Herrmann, David; Allam, Amr; Timpson, Paul; Watkins, D.; Millar, Ewan; O'Toole, Sandra; Gallego-Ortega, David; Ormandy, Christopher; Oakes, Samantha
• Is Part Of: Breast cancer research. Volume 18:Issue 1(2016)
• Page Start: 1
• Page End: 15
• Publication Date: 2016-12
• Subjects: Myeloid cell leukemia-1 -- BIMs2A -- Metastasis -- Invasion -- Breast cancer -- BH3 mimetics -- Cofilin -- SRC family kinase; Breast -- Cancer -- Periodicals; 616.99449
• DOI: 10.1186/s13058-016-0781-6
• Languages: English
• ISSNs: 1465-542X

Abstract

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.