Brown Robert E, Buryanek Jamie, Tammisetti Varaha S, McGuire Mary F, Csencsits-Smith Keri
Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
Oncotarget. 2016 Jul 5;7(27):41612-41621. doi: 10.18632/oncotarget.9508.
It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2.
To combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies.
We applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog.
In patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms.
Morphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs.
有人提出，肾细胞癌（RCC）对雷帕霉素类似物疗法产生耐药性是由于从哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）适应性切换为mTORC2。
结合磷酸化蛋白染色和应用生物医学分析，研究接受雷帕霉素类似物疗法的转移性RCC患者的耐药特征。
我们对9例转移性RCC患者的活检标本进行了形态蛋白质组学分析，这些患者在接受雷帕霉素类似物治疗时肿瘤仍持续出现临床进展。
在活检时接受替西罗莫司或依维莫司治疗的患者中，核区室中磷酸化（p）-mTOR（Ser 2448）的中度至强表达以及p-Akt（Ser 473）的伴随表达证实了mTORC2通路。同时证实了p-ERK 1/2（Thr202/Tyr204）和p-STAT3（Tyr705）的中度至强核表达。5例出现缺氧型凝固性坏死的组织病理学变化，以及在所有研究肿瘤中鉴定出胰岛素样生长因子-1受体（IGF-1R）表达和组蛋白甲基转移酶EZH2，提示缺氧也促成了耐药特征。生物医学分析为可针对此类适应性和致病机制的治疗选择提供了见解。
形态蛋白质组学和生物医学分析证实mTORC2/Akt是转移性RCC对雷帕霉素类似物疗法的耐药特征，并证明促生存ERK和STAT3通路的激活以及缺氧通路的参与，这些通路促成了这种适应性耐药的发病机制。这些结果凸显了对接受雷帕霉素类似物治疗的进展性转移性RCC采用新型联合治疗方法的必要性。
Zotero 插件
