1. MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.
- Author
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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, and Oakes SR
- Subjects
- Animals, Breast Neoplasms drug therapy, Breast Neoplasms mortality, Cell Death drug effects, Cell Death genetics, Cell Line, Tumor, Cell Movement drug effects, Cell Movement genetics, Disease Models, Animal, Female, Gene Expression, Humans, Immunohistochemistry, Mice, Mice, Knockout, Mutation, Myeloid Cell Leukemia Sequence 1 Protein genetics, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Neoplasm Invasiveness, Neoplasm Metastasis, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Dasatinib pharmacology, Drug Resistance, Neoplasm, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- 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.
- Published
- 2016
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