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Published on: May 27, 2021
Coinhibition of Aurora Kinase B and SUV4-20H Induces Synthetic Lethality in Wild-type p53-Deficient Cancer Cells
Lei Duan1, Kelsey M O'Hara1, Andrew Caldemeyer1
1Department of Anatomy and Cell biology, Rush University Medical Center, Chicago, Illinois.
Abstract:
The tumor suppressor p53 is inactivated by mutation or deletion in more than half of all human cancers. Wild-type p53 induces a G1-phase arrest when activated to halt cell proliferation and division. Accordingly, p53-mutated or -deficient cancers may be especially sensitive to agents that target proliferating and/or dividing cells. Barasertib (AZD2811) targets the mitotic Aurora kinase B and is in current clinical trials for various cancers. SUV4-20H1 and H2 are histone methyltransferases that can affect mitosis by regulating chromatin compaction in and around centromeres. The drug A196 inhibits SUV4-20H1 and H2. In the current study, we found combined treatment with barasertib plus A196 induces a pronounced synthetic lethality effect in p53-deficient cancer cells. Mechanistically, we found barasertib plus A196 kills p53-deficient cells by inhibiting the spindle assembly checkpoint and inducing massive chromosome missegregations and toxic aneuploidy. Among breast cancer subtypes, triple-negative breast cancer cells were the most sensitive to this drug combination. Lastly, we found in two different p53-mutated cell line tumor models that barasertib plus A196 has greater antitumor activity than either single agent. Our results suggest cotargeting of Aurora kinase B and SUV4-20H1/2 could be effective against p53-mutated or -deficient cancers, including triple-negative breast cancers in which approximately 80% of cases are p53-mutated.
Insights
Combining barasertib and A196 creates synthetic lethality in p53-deficient cancers by disrupting mitosis. This drug combination shows promise for treating p53-mutated cancers, including triple-negative breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The tumor suppressor p53 is frequently inactivated in human cancers, impacting cell cycle control.
- p53-deficient cancers may be vulnerable to therapies targeting cell proliferation and division.
Purpose of the Study:
- To investigate the efficacy of combined barasertib (AZD2811) and A196 in p53-deficient cancer cells.
- To elucidate the mechanism of action for this drug combination.
Main Methods:
- Treatment of p53-deficient cancer cells with barasertib (Aurora B kinase inhibitor) and A196 (SUV4-20H1/2 inhibitor).
- Assessment of synthetic lethality, cell death, spindle assembly checkpoint inhibition, and chromosome missegregation.
- Evaluation of anti-tumor activity in p53-mutated cell line tumor models.
Main Results:
- Combined barasertib and A196 treatment induced significant synthetic lethality in p53-deficient cancer cells.
- The drug combination inhibited the spindle assembly checkpoint, leading to chromosome missegregation and aneuploidy.
- Triple-negative breast cancer cells showed heightened sensitivity to the combination therapy.
- Barasertib plus A196 demonstrated superior anti-tumor activity compared to single agents in p53-mutated models.
Conclusions:
- Co-targeting Aurora B kinase (AURKB) and SUV4-20H1/2 presents a potential therapeutic strategy for p53-mutated or deficient cancers.
- This approach is particularly relevant for triple-negative breast cancers, where p53 mutations are common.
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