Impact of sunitinib resistance on clear cell renal cell carcinoma therapeutic sensitivity in vitro.

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
ACS Applied Electronic Materials Pub Date : 2024-01-01 Epub Date: 2024-01-23 DOI:10.1080/15384101.2024.2306760
Susmita Ghosh, Mamatha Garige, Patrick R Haggerty, Alexis Norris, Chao-Kai Chou, Wells W Wu, Rong-Fong Shen, Carole Sourbier
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Abstract

Sunitinib resistance creates a major clinical challenge for the treatment of advanced clear cell renal cell carcinoma (ccRCC) and functional and metabolic changes linked to sunitinib resistance are not fully understood. We sought to characterize the molecular and metabolic changes induced by the development of sunitinib resistance in ccRCC by developing and characterizing two human ccRCC cell lines resistant to sunitinib. Consistent with the literature, sunitinib-resistant ccRCC cell lines presented an aberrant overexpression of Axl and PD-L1, as well as a metabolic rewiring characterized by enhanced OXPHOS and glutamine metabolism. Therapeutic challenges of sunitinib-resistant ccRCC cell lines in vitro using small molecule inhibitors targeting Axl, AMPK and p38, as well as using PD-L1 blocking therapeutic antibodies, showed limited CTL-mediated cytotoxicity in a co-culture model. However, the AMPK activator metformin appears to sensitize the effect of PD-L1 blocking therapeutic antibodies and to enhance CTLs' cytotoxic effects on ccRCC cells. These effects were not broadly observed with the Axl and the p38 inhibitors. Taken together, these data suggest that targeting certain pathways aberrantly activated by sunitinib resistance such as the AMPK/PDL1 axis might sensitize ccRCC to immunotherapies as a second-line therapeutic approach.

舒尼替尼耐药性对透明细胞肾细胞癌体外治疗敏感性的影响
舒尼替尼耐药性给晚期透明细胞肾细胞癌(ccRCC)的治疗带来了重大的临床挑战,而与舒尼替尼耐药性相关的功能和代谢变化尚未完全明了。我们试图通过开发和鉴定两种对舒尼替尼耐药的人类ccRCC细胞系,来描述ccRCC中舒尼替尼耐药所引起的分子和代谢变化。与文献报道一致,对舒尼替尼耐药的 ccRCC 细胞系出现了 Axl 和 PD-L1 的异常过表达,以及以 OXPHOS 和谷氨酰胺代谢增强为特征的代谢重构。在体外使用靶向 Axl、AMPK 和 p38 的小分子抑制剂,以及使用 PD-L1 阻断治疗抗体,对耐舒尼替尼的 ccRCC 细胞株进行治疗挑战,在共培养模型中显示出有限的 CTL 介导的细胞毒性。不过,AMPK 激活剂二甲双胍似乎能敏化 PD-L1 阻断治疗性抗体的作用,并增强 CTL 对 ccRCC 细胞的细胞毒作用。在使用 Axl 和 p38 抑制剂时并没有观察到这些效应。综上所述,这些数据表明,针对舒尼替尼耐药性异常激活的某些通路(如 AMPK/PDL1 轴)可能会使 ccRCC 对免疫疗法敏感,从而成为一种二线治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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