Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.
Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.
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DOI：
10.1021/acs.jproteome.1c00550
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发表时间：
2021-12-03
影响因子：
4.4
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Wang XD;Kim C;Zhang Y;Rindhe S;Cobb MH;Yu Y
尽管靶向MAPK通路抑制在许多癌症中实现了显著的患者反应，但耐药性的发展仍然是一个关键挑战。适应性肿瘤反应是耐药性的基础。此外，这种旁路机制通常导致许多促存活激酶的活化，这使得联合疗法的合理设计复杂化。在这里，我们进行了全球酪氨酸磷酸化蛋白质组学（pTyr）分析，并证明，有针对性的MAPK信号抑制在黑色素瘤导致深刻的pTyr蛋白质组的重塑。有趣的是，胆固醇代谢的改变可能以协调的方式驱动这些激酶的激活。事实上，我们发现分别用MAPK和KRASG12C抑制剂处理的黑色素瘤细胞（具有BRAFV600E突变）和非小细胞肺癌细胞（具有KRASG12C突变）中细胞内胆固醇的积累。重要的是，胆固醇的消耗不仅防止pTyr信号传导的反馈激活，而且增强MAPK途径抑制剂的细胞毒性作用，在体外和体内。总之，我们的研究结果表明，胆固醇有助于靶向MAPK通路抑制剂的肿瘤适应性反应。这些结果还表明，MAPK通路抑制剂可以与降胆固醇剂组合，以在具有过度活跃的MAPK信号传导的肿瘤中实现更完整和持久的反应。PRIDE标识符：PXD 021877。
Although targeted MAPK pathway inhibition has achieved remarkable patient responses in many cancers, the development of resistance has remained a critical challenge. Adaptive tumor response underlies the drug resistance. Furthermore, such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted MAPK signaling inhibition in melanoma leads to a profound remodeling of the pTyr proteome. Intriguingly, altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found an accumulation of intracellular cholesterol in melanoma cells (with BRAFV600E mutations) and non-small cell lung cancer cells (with KRASG12C mutations) treated with MAPK and KRASG12C inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the feedback activation of pTyr signaling but also enhances the cytotoxic effects of MAPK pathway inhibitors, both in vitro and in vivo. Together, our findings suggest that cholesterol contributes to the tumor adaptive response upon targeted MAPK pathway inhibitors. These results also suggest that MAPK pathway inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling. PRIDE identifier: PXD021877.
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DOI：
10.2183/pjab.86.484
发表时间：
2010
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Endo A
通讯作者：
Endo A
影响因子：
2.9
作者：
Cerqueira, Nuno M. F. S. A.;Oliveira, Eduardo F.;Fernandes, P. A.
通讯作者：
Fernandes, P. A.
影响因子：
14.9
作者：
Hornbeck PV;Kornhauser JM;Tkachev S;Zhang B;Skrzypek E;Murray B;Latham V;Sullivan M
通讯作者：
Sullivan M
影响因子：
4.6
作者：
Chou, Cheng-Wei;Lin, Ching-Heng;Sher, Yuh-Pyng
通讯作者：
Sher, Yuh-Pyng
影响因子：
11.2
作者：
Lin, Yi-Chu;Lin, Jung-Hsin;Chen, Ching-Chow
通讯作者：
Chen, Ching-Chow