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.

中文翻译：

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利用 p53 突变体在肺癌中的脆弱性——专注于蛋白酶体：老对手的新伎俩？

功能获得性 (GOF) p53 突变通常发生在人类癌症中，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 突变体 p53 的致癌性与其相对于野生型 p53 的异常蛋白质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。我们回顾了证明蛋白酶体抑制剂对 GOF p53 的反常消耗的临床前证据，以及蛋白酶体抑制在肺癌中的临床前和临床研究。最后，我们提供了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。