Smith, J.C.; Husted, S.; Pilrose, J.; Ems-McClung, S.C.; Stout, J.R.; Carpenter, R.L.; Walczak, C.E. MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models. Cancers2023, 15, 3309.
Smith, J.C.; Husted, S.; Pilrose, J.; Ems-McClung, S.C.; Stout, J.R.; Carpenter, R.L.; Walczak, C.E. MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models. Cancers 2023, 15, 3309.
Smith, J.C.; Husted, S.; Pilrose, J.; Ems-McClung, S.C.; Stout, J.R.; Carpenter, R.L.; Walczak, C.E. MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models. Cancers2023, 15, 3309.
Smith, J.C.; Husted, S.; Pilrose, J.; Ems-McClung, S.C.; Stout, J.R.; Carpenter, R.L.; Walczak, C.E. MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models. Cancers 2023, 15, 3309.
Abstract
Standard of care for triple negative breast cancer (TNBC) involves the use of microtubule poisons like 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 50k 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.
Keywords
triple negative breast cancer; MCAK/KIF2C; aneuploidy; chromosomal instability; drug discovery
Subject
Biology and Life Sciences, Cell and Developmental Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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