Harnessing the vulnerabilities of p53 mutants in lung cancer - Focusing on the proteasome: a new trick for an old foe?

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.

Keywords: P53 mutation; gain-of-function; lung cancer; proteasome; proteasome inhibitors; stability.

Figure 1.

Wildtype p53 is a tumor suppressor while mutant p53 acquires gain-of-function (GOF) oncogenic activities implicated in several hallmarks of cancer.

Figure 2.

Wild type p53 is readily degraded by the proteasome through a multistep process of ubiquitination mediated primarily through the E3 ligase Murine Double Minute 2 (MDM2) and other E4 ligases. Mutant p53 (Mut-p53) evades proteasomal degradation likely due to defective ubiquitination and recognition by the proteasome machinery.