MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models
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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Cancers - 15(2023), 13 vom: 23. Juni |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Smith, John C [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Aneuploidy |
|---|
| Anmerkungen: |
Date Revised 29.01.2024 published: Electronic UpdateOf: bioRxiv. 2023 Jun 01;:. - PMID 37397990 Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/cancers15133309 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359451640 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359451640 | ||
| 003 | DE-627 | ||
| 005 | 20240129231837.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/cancers15133309 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1274.xml |
| 035 | |a (DE-627)NLM359451640 | ||
| 035 | |a (NLM)37444419 | ||
| 035 | |a (PII)3309 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Smith, John C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MCAK Inhibitors Induce Aneuploidy in Triple-Negative Breast Cancer Models |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 29.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Jun 01;:. - PMID 37397990 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a MCAK/KIF2C | |
| 650 | 4 | |a aneuploidy | |
| 650 | 4 | |a chromosomal instability | |
| 650 | 4 | |a drug discovery | |
| 650 | 4 | |a triple-negative breast cancer | |
| 700 | 1 | |a Husted, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Pilrose, Jay |e verfasserin |4 aut | |
| 700 | 1 | |a Ems-McClung, Stephanie C |e verfasserin |4 aut | |
| 700 | 1 | |a Stout, Jane R |e verfasserin |4 aut | |
| 700 | 1 | |a Carpenter, Richard L |e verfasserin |4 aut | |
| 700 | 1 | |a Walczak, Claire E |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancers |d 2009 |g 15(2023), 13 vom: 23. Juni |w (DE-627)NLM198667213 |x 2072-6694 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2023 |g number:13 |g day:23 |g month:06 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/cancers15133309 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2023 |e 13 |b 23 |c 06 | ||