Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and epidermal growth factor receptor (EGFR), which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR co-inhibition using a multifaceted approach to analyze the global phosphoproteome and chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a highly synergistic antitumor effect. Notably, the combined inhibition strategy activated the DNA damage response, induced G1 cell cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6 (CDC6), a crucial initiator of DNA replication. Together, this study offers preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer that disrupts DNA synthesis by impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes.

中文翻译：

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SYK 和 EGFR 的双重抑制通过抑制 CDC6 和阻断 DNA 复制来克服化疗耐药性


靶向多个信号通路已被提议作为克服癌症治疗中对单通路抑制的耐药性的策略。先前对上皮性卵巢癌的一项研究确定了脾酪氨酸激酶 （SYK） 和表皮生长因子受体 （EGFR） 的过度活跃，它们相互磷酸化并相互激活。鉴于临床可用药物对两种激酶的药物抑制潜力，本研究旨在评估药物和遗传 SYK 和 EGFR 共同抑制的抗肿瘤疗效，使用多方面的方法来分析全球磷酸化蛋白质组和化疗耐药卵巢癌细胞系、患者来源的类器官和异种移植模型。化疗耐药卵巢癌细胞中 SYK 和 EGFR 的双重抑制引发了高度协同的抗肿瘤作用。值得注意的是，联合抑制策略激活了 DNA 损伤反应，诱导 G1 细胞周期停滞，并促进了细胞凋亡。磷酸化蛋白质组学分析显示，SYK 和 EGFR 信号传导的扰动诱导细胞分裂周期 6 （CDC6） 的磷酸化和总蛋白水平显著降低，这是 DNA 复制的关键启动因子。总之，这项研究提供了临床前证据，支持 SYK 和 EGFR 的双重抑制是一种很有前途的化疗耐药卵巢癌治疗方法，该卵巢癌通过损害复制前复合物的形成来破坏 DNA 合成。这些发现值得进一步的临床研究，以探索这种联合疗法在克服耐药性和改善患者预后方面的潜力。