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

Abstract

BackgroundMetastatic 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.MethodsTo 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.ResultsMCL-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.ConclusionThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0781-6) contains supplementary material, which is available to authorized users.

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

“…Cyclin E1 was mutated by site-directed mutagenesis as described (18). MDA-MB-468 cells expressing the ecotropic receptor (19) were infected with pMSCV-IRES-GFP retrovirus expressing cyclin E1 wildtype and mutants as described (20). Subpopulations with graded expression of GFP and cyclin proteins were separated by sterile FACS and matched populations selected based on GFP expression.…”

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…Of note, $85% of ER-positive breast cancers express high levels of BCL-2 (Dawson et al, 2010) and, accordingly, venetoclax and navitoclax synergized with tamoxifen in inhibiting the growth of patient-derived xenografts in mice (Vaillant et al, 2013). MCL-1 inhibitors, such as S63845, were also shown to efficiently inhibit the growth of triple-negative as well as HER-2-positive breast cancers when combined with chemotherapy or HER2-targeted therapies (Kotschy et al, 2016;Leverson et al, 2015b;Merino et al, 2017;Xiao et al, 2015;Young et al, 2016). Neuroblastoma growth was attenuated by inhibition of either BCL-2 or MCL-1 (Bate-Eya et al, 2016;Tanos et al, 2016), and the combination of venetoclax with the aurora kinase A inhibitor MLN8237 achieved complete remission in a patientderived xenograft of MYCN-amplified neuroblastomas (Ham et al, 2016).…”

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

“…MCL1 is a prosurvival gene and a member of the BCL2 family, which governs the intrinsic apoptotic pathway (33) and has been shown to be highly expressed in some breast cancers, playing an important role in patient response to antitubulin chemotherapeutics (34). MCL1 expression has been associated with metastasis in colorectal (35), gastric (36,37), and breast cancers (38)(39)(40). Our study also identified aberrations of several other genes or chromosome regions that were enriched in ER + breast cancer patients with versus those without lymph node metastasis, including gains of chr12q and chr20q and losses of chr1p and chr9p, most of whose copy number alteration (CNA) have not previously been associated with breast cancer metastasis ( Figure 6B).…”