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 M.; Gorodetsky, Elizabeth F.; Karakousi, Triantafyllia; Hirsh, Nicole; Alvarez, Samantha; Terzi, Erdem M.; Kaparos, Efiyenia I.; 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 29 publications

(24 citation statements)

References 63 publications

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“…Interestingly, phosphoproteomic analyses have demonstrated T487 phosphorylation significantly elevated in basal-like breast cancers compared to other subtypes 84 , suggesting a context-specific role for this event.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer

Anwar

González

Kleer

2021

The American Journal of Pathology

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer

Anwar

González

Kleer

2021

The American Journal of Pathology

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“…Moreover, mutations in the cyclin-dependent kinase gene, CDC28, restore near-normal growth characteristics of strains without the catalytic half of Pol2, implying that cell cycle control machinery can facilely accommodate for its absence [54]. The connection between CDKs and pol ε has also been demonstrated for breast cancer cell lines [55].…”

Section: The Cornerstone Model Of the Replication Forkmentioning

confidence: 95%

“…The Fe-S cluster in the catalytic subunit of pol ε was found in an unusual location: in the N-terminal half in the vicinity of pol II motif (Figure 1), structurally characterized, and shown to be necessary for pol but not exo activity in functional assays [80,81]. A recent study revealed the unique sensitivity of pol ε to suppression of Fe-S biosynthesis in basal-like breast cancer cell lines [55].…”

Section: Progress On the Structure-function Of B-family Dna Polymerasmentioning

confidence: 99%

DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer

Pavlov

Zhuk

Stepchenkova

2020

Cancers

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Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication fork organization. The principal idea of participation of different polymerases in specific transactions at the fork proposed by Morrison and coauthors 30 years ago and later named “division of labor,” remains standing, with an amendment of the broader role of polymerase δ in the replication of both the lagging and leading DNA strands. However, cancer-associated mutations predominantly affect the catalytic subunit of polymerase ε that participates in leading strand DNA synthesis. We analyze how new findings in the DNA replication field help elucidate the polymerase variants’ effects on cancer.

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“…Future studies are needed to clarify whether BCL-XL+CDK1/2/4 inhibition would also minimize heterogeneous mechanisms of resistance otherwise occurring by targeting CDK4/6 with chemotherapeutics previously reported [40]. [41]. Additionally, CDK1 phosphorylates several proteins involved in epigenetic regulation, such as the H3K79 methyltransferase Dot1l, responsible for placing activating marks on gene bodies [42].…”

Section: Discussionmentioning

confidence: 99%

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

Castellanet

Ahmad

Vinik

et al. 2021

Preprint

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Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of BCL-XL and specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

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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

Cited by 29 publications

References 63 publications

Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer

Noncanonical Functions of the Polycomb Group Protein EZH2 in Breast Cancer

DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

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