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? Cancer Biol Ther. 2020 Feb 10;:1-10 Authors: Oduah EI, Grossman SR Abstract 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. PMID: 32041464 [PubMed - as supplied by publisher]
Source: Cancer Biology and Therapy - Category: Cancer & Oncology Authors: Tags: Cancer Biol Ther Source Type: research