PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI-Resistant Metastatic Clear Cell Renal Cell Carcinoma.
PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI-Resistant Metastatic Clear Cell Renal Cell Carcinoma.
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VEGFR-TKI耐药转移性透明细胞肾细胞癌中mTOR通路的PD-L1上调
DOI：
10.4143/crt.2021.1526
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发表时间：
2023-01
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
针对血管内皮生长因子受体(VEGFR)信号通路的酪氨酸激酶抑制剂(TKI)已用于转移性透明细胞肾癌(MCCRCC)，但大多数患者对该药物产生耐药性。本研究旨在探讨TKI对程序性死亡配体1(PD-L1)耐药的机制，并探讨与耐药机制相关的信号转导途径。为了确定耐药机制，选择10例在治疗前和治疗后TKI耐药期间均获得肿瘤组织的mCCRCC患者作为发现队列，比较它们的整体基因表达谱。通过长期应用舒尼替尼，建立了TKI耐药的肾癌细胞株。在发现的队列中差异表达的基因中，有4名患者在治疗后组织中发现PD-L1表达增加。通路分析表明，PD-L1的表达与哺乳动物雷帕霉素靶点(MTOR)信号通路呈正相关。对TKI耐药的肾癌细胞显示PD-L1和mTOR信号蛋白表达增加，并表现出侵袭性肿瘤行为。用mTOR抑制剂治疗可下调PD-L1的表达，并抑制侵袭性肿瘤行为，这一点可通过刺激mTOR途径而逆转。这些结果表明，在VEGFR-TKI耐药的mCCRCC患者中，PD-L1的表达可能通过mTOR途径增加。
Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism. To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib. Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway. These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.
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影响因子：
23.4
作者：
Moch, Holger;Cubilla, Antonio L.;Ulbright, Thomas M.
通讯作者：
Ulbright, Thomas M.
通过与染料木黄酮和雌二醇孵育，在前列腺癌细胞中低剂量超Xiosistitive的修饰的体外研究。
影响因子：
3.6
作者：
Hermann, Robert Michael;Wolff, Hendrik Andreas;Jarry, Hubertus;Thelen, Paul;Gruendker, Carsten;Rave-Fraenk, Margret;Schmidberger, Heinz;Christiansen, Hans
通讯作者：
Christiansen, Hans
DOI：
10.1200/jco.20.02365
发表时间：
2021-03-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
McDermott DF;Lee JL;Ziobro M;Suarez C;Langiewicz P;Matveev VB;Wiechno P;Gafanov RA;Tomczak P;Pouliot F;Donskov F;Alekseev BY;Shin SJ;Bjarnason GA;Castellano D;Silverman RK;Perini RF;Schloss C;Atkins MB
通讯作者：
Atkins MB
影响因子：
64.5
作者：
Lichtenberger, Beate M.;Tan, Poi Kiang;Sibilia, Maria
通讯作者：
Sibilia, Maria
影响因子：
6.4
作者：
Lee, Kyu Sang;Choe, Gheeyoung;Lee, Sang Eun
通讯作者：
Lee, Sang Eun