Harnessing the vulnerabilities of p53 mutants in lung cancer - Focusing on the proteasome: a new trick for an old foe?
Harnessing the vulnerabilities of p53 mutants in lung cancer - Focusing on the proteasome: a new trick for an old foe?
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DOI：
10.1080/15384047.2019.1702403
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发表时间：
2020-04-02
影响因子：
3.6
通讯作者：
Grossman SR
中科院分区：
文献类型：
--
作者：
Oduah EI;Grossman SR
功能获得（GOF） p53突变在人类癌症中很常见，并导致p53肿瘤抑制功能的丧失和侵袭性癌症表型的获得。GOF突变型p53的致癌性与其相对于野生型p53的异常蛋白稳定性和总体化学计量过量高度相关。我们概述了GOF p53功能障碍和异常稳定性的机制，特别是在肺癌中，肺癌是癌症相关死亡的主要原因，其中，根据组织学亚型，33-90%的肿瘤表现出GOF p53突变。作为肺癌和许多其他癌症的显着特征和致癌机制，GOF p53代表了一个有吸引力的癌症特异性治疗靶点。我们回顾了临床前证据，证明蛋白酶体抑制剂对GOF p53的矛盾消耗，以及蛋白酶体抑制肺癌的临床前和临床研究。最后，我们提供了一个重新检查肺癌中蛋白酶体抑制的基本原理，重点是表达GOF p53等位基因的肿瘤。
Gain-of-function (GOF) p53 mutations occur commonly in human cancer and lead to both loss of p53 tumor suppressor function and acquisition of aggressive cancer phenotypes. The oncogenicity of GOF mutant p53 is highly related to its abnormal protein stability relative to wild type p53, and overall stoichiometric excess. We provide an overview of the mechanisms of dysfunction and abnormal stability of GOF p53 specifically in lung cancer, the leading cause of cancer-related mortality, where, depending on histologic subtype, 33-90% of tumors exhibit GOF p53 mutations. As a distinguishing feature and oncogenic mechanism in lung and many other cancers, GOF p53 represents an appealing and cancer-specific therapeutic target. We review preclinical evidence demonstrating paradoxical depletion of GOF p53 by proteasome inhibitors, as well as preclinical and clinical studies of proteasome inhibition in lung cancer. Finally, we provide a rationale for a reexamination of proteasome inhibition in lung cancer, focusing on tumors expressing GOF p53 alleles.
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影响因子：
4.6
作者：
Denlinger, CE;Rundall, BK;Jones, DR
通讯作者：
Jones, DR
影响因子：
4.3
作者：
Choudhury, Sujata;Kolukula, Vamsi K.;Avantaggiati, Maria Laura
通讯作者：
Avantaggiati, Maria Laura
影响因子：
64.8
作者：
Alexandrova EM;Yallowitz AR;Li D;Xu S;Schulz R;Proia DA;Lozano G;Dobbelstein M;Moll UM
通讯作者：
Moll UM
DOI：
10.1097/jto.0b013e3181915052
发表时间：
2009-01
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Davies AM;Chansky K;Lara PN Jr;Gumerlock PH;Crowley J;Albain KS;Vogel SJ;Gandara DR;Southwest Oncology Group
通讯作者：
Southwest Oncology Group
影响因子：
1.8
作者：
Drilon, Alexander;Schoenfeld, Adam J.;Riely, Gregory J.
通讯作者：
Riely, Gregory J.