携带 TP53 突变的胃癌患者表现出更具侵袭性和化疗耐药性的表型。不幸的是，近年来，识别脆弱性以克服这些侵袭性恶性肿瘤的努力进展甚微。因此，迫切需要探索该亚类的新治疗策略。组蛋白甲基化调节剂是癌症治疗的关键表观遗传靶标，有助于维持携带 TP53 突变和衰老逃避的癌症的恶性程度。现在认为触发衰老有利于多种癌症治疗。此外，基于衰老的“一两拳”疗法在临床试验中得到了验证。因此，我们假设筛选表观遗传调节剂可能有助于识别携带 TP53 突变的胃癌中触发衰老的新脆弱性。我们开发了一种新的有效方法，通过用候选药物和衰老抑制剂顺序处理细胞来识别衰老诱导剂。基于此，我们证明了 QC6352（一种选择性 KDM4C 抑制剂）可有效引发携带 TP53 突变的胃癌细胞衰老。更重要的是，由QC6352和SSK1组成的“一两拳”疗法消除了携带TP53突变的肿瘤细胞。这一发现凸显了针对侵袭性胃癌亚组的潜在治疗策略。此外，QC6352的功能完全未知。我们证明了与传统的基因毒性药物5-Fu和奥沙利铂相比，QC6352可能具有更强大的抗肿瘤能力。这项鉴定衰老诱导剂的初步研究表明，QC6352通过调节SP1/CDK2触发携带TP53突变的胃癌细胞的衰老通过抑制 KDM4C 来抑制 KDM4C 轴。QC6352 和 senolytic agent-SSK1 代表了一种针对恶性程度更高的胃癌亚型的新型“一两拳”治疗策略。© 2023。BioMed Central Ltd.，Springer Nature 旗下公司。

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.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.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.© 2023. BioMed Central Ltd., part of Springer Nature.