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KDM4C-mediated senescence defense is a targetable vulnerability in gastric cancer harboring TP53 mutations
Kaiqing Wang1,2,3, Zhicheng Gong4,5, Yanyan Chen2,3
1Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China.
Background:
Gastric cancer patients harboring a TP53 mutation exhibit a more aggressive and chemoresistant phenotype. Unfortunately, efforts to identify the vulnerabilities to overcome these aggressive malignancies have made minimal progress in recent years. Therefore, there is an urgent need to explore the novel therapeutic strategies for this subclass. Histone methylation modulators are critical epigenetic targets for cancer therapies that help maintain the malignancies of cancers harboring TP53 mutations and senescence evasion. Triggering senescence is now considered to benefit multiple cancer therapies. Furthermore, senescence-based "one-two punch" therapy was validated in clinical trials. Therefore, we hypothesized that screening epigenetic modulators might help identify a novel vulnerability to trigger senescence in gastric cancer harboring TP53 mutations.
Results:
We developed a novel efficient approach to identify senescence inducers by sequentially treating cells with drug candidates and senolytic agents. Based on this, we demonstrated that QC6352 (a selective KDM4C inhibitor) efficiently triggered cellular senescence in gastric cancer harboring TP53 mutations. More importantly, the "one-two punch' therapy consisting of QC6352 and SSK1 eliminates tumor cells harboring TP53 mutations. This finding highlights a potential therapeutic strategy for the aggressive subgroup of gastric cancer. Besides, the functions of QC6352 were totally unknown. We demonstrated that QC6352 might possess far more powerful anti-tumor capacities compared to the traditional genotoxic drugs, 5-Fu and Oxaliplatin.
Conclusions:
This initial investigation to identify a senescence inducer revealed that QC6352 triggers senescence in gastric cancer cells harboring TP53 mutations by regulating the SP1/CDK2 axis through suppressing KDM4C. QC6352 and senolytic agent-SSK1 represent a novel 'one-two punch' therapeutic strategy for the more malignant gastric cancer subtypes.
Insights
A novel KDM4C inhibitor, QC6352, triggers senescence in TP53-mutated gastric cancer. Combined with senolytic agent SSK1, this offers a promising "one-two punch" therapy for aggressive gastric cancer subtypes.
Area of Science:
- Oncology
- Epigenetics
- Cancer Therapy
Background:
- Gastric cancer with TP53 mutations is aggressive and chemoresistant.
- Limited progress in identifying therapeutic vulnerabilities for this subtype.
- Epigenetic modulators targeting histone methylation are crucial for managing cancers with TP53 mutations and senescence evasion.
Purpose of the Study:
- To explore novel therapeutic strategies for TP53-mutated gastric cancer.
- To identify epigenetic modulators that can trigger senescence in this aggressive cancer subtype.
- To investigate the potential of senescence-based therapies for gastric cancer.
Main Methods:
- Developed a novel sequential drug treatment approach to identify senescence inducers.
- Screened epigenetic modulators for their ability to induce senescence.
- Evaluated the efficacy of a combination therapy using a KDM4C inhibitor and a senolytic agent.
Main Results:
- QC6352, a selective KDM4C inhibitor, effectively triggered cellular senescence in TP53-mutated gastric cancer cells.
- The combination of QC6352 and the senolytic agent SSK1 eliminated tumor cells harboring TP53 mutations.
- QC6352 demonstrated potent anti-tumor capacities, potentially exceeding those of traditional genotoxic drugs like 5-Fu and Oxaliplatin.
Conclusions:
- QC6352 induces senescence in TP53-mutated gastric cancer by regulating the SP1/CDK2 axis via KDM4C suppression.
- The combination of QC6352 and SSK1 represents a novel 'one-two punch' therapeutic strategy for aggressive gastric cancer.
- This approach offers a potential new treatment avenue for the challenging TP53-mutated gastric cancer subgroup.
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