Molecularly targeted therapies for p53-mutant cancers

Abstract

The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

“…Thus, for the two last decades, numerous compounds were identified to destabilize highly accumulated GOF p53 mutants, or to reverse the oncogenic properties of mutp53 ( Figure 1 and Table 1 ) (also reviewed in [ 6 , 7 , 19 , 20 , 63 ]). Besides strategies to directly target stabilized mutp53 for degradation or reactivation by restoring a ‘wild-type-like’ conformation, many approaches are indirect, suggesting to (I) exploit tumor cell vulnerabilities that result from missense mutp53-specific signaling to downstream pathways [ 7 , 20 , 64 ], (II) inhibit the remaining G2 checkpoint on which such tumor cells depend, since wtp53-deficient tumors have lost their G1 checkpoint [ 20 , 64 ], (III) target mutp53-mediated metabolic pathways [ 64 , 65 ] and (IV) inhibit mutp53 interactors that accelerate cancer progression [ 7 , 20 , 64 ].…”

“…This is human-relevant, since the majority of human mutp53 tumors undergo loss-of-heterozygosity (LOH). GOF mutants represent a phenotypic spectrum and depend on tumor context, described in several excellent recent reviews [ 6 , 7 , 16 , 17 , 18 , 19 , 20 ]. Taken together, targeting cancer-associated mutp53 GOF functions is a highly promising rational approach that strikes cancer cells selectively, with low toxicity in healthy tissues.…”

Patterns of mutations in TP53 mutated AML

“…It is unclear at this time whether these will necessarily be mutation specific, or whether drugs can be developed that will destabilize diverse mutant forms. In addition, there has been interest in identifying pathways that become necessary for cell survival in the presence of TP53 mutations, as these could function as synthetic lethality strategies [58]. This may offer an alternative approach, although it will be important to determine whether these strategies result in cell-type specificity or if they might become effective across diverse cancer cell types.…”

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

“…1). Despite the central role of TP53 in HNSCC carcinogenesis (2), to date no standard-of-care therapy leverages the tumor's p53 status, albeit preclinical work, and clinical trials are bringing this goal closer (3)(4)(5). We have previously found that inhibition of the cell-cycle kinase WEE1 with a small-molecule AZD1775 is significantly more cytotoxic to p53-mutated than to p53 WT HNSCC cell lines (6).…”