Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.

中文翻译：

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同时抑制 ALK 和 SRC 激酶会破坏 ALK 肺肿瘤细胞蛋白质组


精准肿瘤学通过靶向治疗彻底改变了 ALK 阳性肺癌的治疗方法。然而，仍有待解决的未满足的临床需求是治疗难治性肿瘤，这些肿瘤在驱动癌基因中含有药物诱导的耐药突变或通过激活不同的机制表现出耐药性。在这项研究中，我们建立了代表人类肺腺癌中两种最常见变异的小鼠肿瘤衍生细胞模型，并表征了它们的蛋白质组谱，以深入了解潜在的耐药机制。我们发现变体 3 对 ALK 抑制剂的反应较差，这表明它在促进靶向治疗耐药性方面发挥了作用。此外，对布加替尼处理的细胞的蛋白质组学分析揭示了 SRC 激酶的上调，SRC 激酶是一种在癌症中经常激活的蛋白质。 ALK 和 SRC 的共同靶向对 ALK 驱动的小鼠和 ALK 患者来源的肺肿瘤细胞均显示出显着的抑制作用。这种组合通过多方面的机制诱导细胞死亡，其特征是对（磷酸）蛋白质组景观的深刻扰动和对 mTOR 通路的协同抑制作用。我们的研究表明，同时抑制 ALK 和 SRC 可以潜在地克服耐药机制并增强 ALK 阳性肺癌患者的临床结果。共同靶向 ALK 和 SRC 通过影响蛋白质组谱来增强肺癌中 ALK 抑制剂的反应，为克服耐药性和改善临床结果带来希望。