靶向多信号通路已被提议作为克服癌症治疗中单通路抑制耐药性的策略。先前的一项针对上皮性卵巢癌的研究发现，脾酪氨酸激酶（SYK）和表皮生长因子受体（EGFR）过度活跃，它们相互磷酸化并相互激活。鉴于临床上可用的药物对这两种激酶进行药理学抑制的潜力，本研究旨在使用多方面的方法来分析整体磷酸化蛋白质组和化疗耐药性卵巢癌细胞系，以评估药物和遗传 SYK 和 EGFR 共同抑制的抗肿瘤功效。 -衍生的类器官和异种移植模型。在化疗耐药的卵巢癌细胞中双重抑制 SYK 和 EGFR 会产生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，并促进细胞凋亡。磷酸化蛋白质组学分析表明，SYK 和 EGFR 信号传导的扰动会导致细胞分裂周期 6 (CDC6)（DNA 复制的关键启动子）的磷酸化蛋白和总蛋白水平显着降低。总之，这项研究提供了临床前证据，支持 SYK 和 EGFR 的双重抑制作为化疗耐药性卵巢癌的一种有前途的治疗方法，通过损害预复制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。

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.