Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Qingdao Institute, Institutes of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, 200433, China.
Department of Oncology, Shanghai Medical College, Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China.
Nat Commun. 2023 Jul 17;14(1):4274. doi: 10.1038/s41467-023-39981-6.
The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.
酪氨酸激酶抑制剂（TKI）舒尼替尼是一种被批准用于治疗晚期肾细胞癌的疗法。在这里，我们对 115 例接受舒尼替尼治疗的透明细胞肾细胞癌（ccRCC）患者的肿瘤进行了蛋白质基因组学分析，揭示了 TKI 治疗中不同临床结果的分子基础。我们发现，7q 染色体增益诱导的 mTOR 信号激活与舒尼替尼治疗效果不佳有关，而马兜铃酸特征和 VHL 突变协同导致的糖酵解增强与较好的预后相关。蛋白质组学和磷酸化蛋白质组学分析进一步强调了 mTOR 信号对舒尼替尼无反应的责任。免疫景观特征揭示了 ccRCC 中不同的肿瘤微环境亚群。最后，我们构建了一个多组学分类器，可以检测出应答者和无应答者患者（接收者操作特征曲线下面积，0.98）。我们的研究强调了 ccRCC 分子特征与 TKI 反应之间的关联，这有助于未来改善治疗反应。
