Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε

Sviderskiy, Vladislav O.; Blumenberg, Lili; Gorodetsky, Elizabeth; Karakousi, Triantafyllia R.; Hirsh, Nicole; Alvarez, Samantha W.; Terzi, Erdem M.; Kaparos, Efiyenia; Whiten, Gabrielle C.; Ssebyala, Shakirah; Tonzi, Peter; Mir, Hannan; Neel, Benjamin G.; Huang, Tony T.; Adams, Sylvia; Ruggles, Kelly V.; Possemato, Richard

doi:10.1016/j.molcel.2020.10.016

Cited by 56DNA Repair MechanismsBreast Cancer Treatment StudiesCancer-related Molecular Pathways

Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε

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Sviderskiy, Vladislav O., Blumenberg, Lili, Gorodetsky, Elizabeth, Karakousi, Triantafyllia R., Hirsh, Nicole, Alvarez, Samantha W., Terzi, Erdem M., Kaparos, Efiyenia +9 more·2020·Molecular Cell

DOI 10.1016/j.molcel.2020.10.016PMC PMC7687292

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Abstract

Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

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Cells require functional NFS1 to support iron-sulfur cluster synthesis to maintain viability and proliferation.
“cells require functional NFS1 to support ISC synthesis to maintain viability and proliferation (30, 34)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [34]
The Introduction identifies NFS1 as a key enzyme in ISC synthesis, and the Results show that suppressing it reduces ISC proteins and impairs proliferation in basal-like breast cancer cells. The claim extends the viability and proliferation requirement to cells generally, whereas the Results report substantially stronger growth inhibition in basal-like cells than in other breast-cell subtypes. Page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Low oxygen conditions allow cells to proliferate in the absence of NFS1.
“which allows cells to proliferate in the absence of NFS1 (30, 34)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [34]
The Results section ('Partial Suppression of ISC Biosynthesis'; page unavailable) says that 3% oxygen rescues proliferation defects caused by ISC biosynthesis inhibition and reports restored cell-cycle profiles in cells expressing NFS1 shRNAs. Those experiments suppress NFS1; they do not establish that cells proliferate when NFS1 is entirely absent. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Iron-sulfur clusters are sensitive to degradation under atmospheric oxygen conditions (21% O2).
“ISCs are sensitive to degradation under atmospheric oxygen conditions (standard tissue culture is 21% O2)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [34]
A cyclin-dependent kinase 2 inhibitor protects against the cell proliferation defect induced by suppression of the ISC-containing protein DNA polymerase epsilon.
“a cyclin-dependent kinase 2 inhibitor, which was recently demonstrated to protect against the cell proliferation defect induced by suppression of the ISC-containing protein, DNA polymerase epsilon (34)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [34]
Iron-sulfur clusters are stabilized under low oxygen conditions (3% O2).
“ISCs are stabilized under low oxygen conditions (3% O2)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [34]

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Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon
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Authors: Sviderskiy, V. O., Blumenberg, L., Gorodetsky, E., Karakousi, T. R., Hirsh, N., Alvarez, S. W., Terzi, E. M., Kaparos, E., Whiten, G. C., Ssebyala, S., Tonzi, P., Mir, H., Neel, B. G., Huang, T. T., Adams, S., Ruggles, K. V., & Possemato, R.
Affiliations: NYU Langone Health (US)
NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
Corresponding author: Possemato, Richard
ORCID: Sviderskiy, Vladislav O.
Blumenberg, Lili
Gorodetsky, Elizabeth
Karakousi, Triantafyllia R.
Hirsh, Nicole
Terzi, Erdem M.
Kaparos, Efiyenia
Whiten, Gabrielle C.
Ssebyala, Shakirah
Mir, Hannan
Neel, Benjamin G.
Huang, Tony T.
Adams, Sylvia
Ruggles, Kelly V.
Possemato, Richard
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2020-11
Volume: 80
Issue: 4
Pages: 682-698.e7
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2020.10.016
PMC: PMC7687292
OpenAlex: W3097765978
Cited by: 56
References: 66
Citations by year: 2026: 13 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 1
FWCI: 1.78
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Pew Charitable Trusts
Alexander and Margaret Stewart Trust
American Cancer Society
Susan G. Komen for the Cure
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: basal-like breast cancer, DNA polymerase epsilon, poles, iron-sulfur cluster assembly, genomic instability, DNA damage response, replication fork stalling, senescence, luminal breast cancer, hyperphosphorylation
MeSH terms: Poly-ADP-Ribose Binding Proteins, Animals, Breast Neoplasms, Basal Cell Carcinoma, Cell Cycle, DNA Damage, DNA Polymerase II, Female, Humans, Phosphorylation, Tumor Cells, Cultured, Signal Transduction, Mice, Inbred NOD, Apoptosis, Genomic Instability, Cell Proliferation, Cyclin-Dependent Kinase 2, Mice

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Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε

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