MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models
Author:
Smith John C.1ORCID, Husted Stefan2, Pilrose Jay3, Ems-McClung Stephanie C.1ORCID, Stout Jane R.1, Carpenter Richard L.1, Walczak Claire E.1ORCID
Affiliation:
1. Medical Sciences, Indiana School of Medicine—Bloomington, Bloomington, IN 47405, USA 2. LabCorp Drug Development Indianapolis, Indianapolis, IN 46214, USA 3. Catalent Pharma Solutions Bloomington, Bloomington, IN 47403, USA
Abstract
Standard of care for triple-negative breast cancer (TNBC) involves the use of microtubule poisons such as paclitaxel, which are proposed to work by inducing lethal levels of aneuploidy in tumor cells. While these drugs are initially effective in treating cancer, dose-limiting peripheral neuropathies are common. Unfortunately, patients often relapse with drug-resistant tumors. Identifying agents against targets that limit aneuploidy may be a valuable approach for therapeutic development. One potential target is the microtubule depolymerizing kinesin, MCAK, which limits aneuploidy by regulating microtubule dynamics during mitosis. Using publicly available datasets, we found that MCAK is upregulated in triple-negative breast cancer and is associated with poorer prognoses. Knockdown of MCAK in tumor-derived cell lines caused a two- to five-fold reduction in the IC50 for paclitaxel, without affecting normal cells. Using FRET and image-based assays, we screened compounds from the ChemBridge 50 k library and discovered three putative MCAK inhibitors. These compounds reproduced the aneuploidy-inducing phenotype of MCAK loss, reduced clonogenic survival of TNBC cells regardless of taxane-resistance, and the most potent of the three, C4, sensitized TNBC cells to paclitaxel. Collectively, our work shows promise that MCAK may serve as both a biomarker of prognosis and as a therapeutic target.
Subject
Cancer Research,Oncology
Reference89 articles.
1. Context is everything: Aneuploidy in cancer;Amon;Nat. Rev. Genet.,2019 2. The multifaceted role of chromosomal instability in cancer and its microenvironment;Bakhoum;Cell,2018 3. DNA breaks and chromosome pulverization from errors in mitosis;Crasta;Nature,2012 4. Papathanasiou, S., Mynhier, N.A., Liu, S., Jacob, E., Stokasimov, E., Steensel, B., Zhang, C., and Pellman, D. (2022). Transgenerational transcriptional heterogeneity from cytoplasmic chromatin. BioRxiv. 5. Agustinus, A.S., Al-Rawi, D., Dameracharla, B., Raviram, R., Jones, B.S.C.L., Stransky, S., Scipioni, L., Luebeck, J., Di Bona, M., and Norkunaite, D. (2023). Epigenetic dysregulation from chromosomal transit in micronuclei. Nature, Epub ahead of print.
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