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 also 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.

Keywords: Gain of function; Survival pathway; Targeted therapies; p53 mutation.

Fig. 1

Strategies to target mutant p53 in cancers. Two approaches have been used to target mutant p53 for cancer treatment. The first approach is to using small molecular compounds to directly target mutant p53 by induction of its degradation or reactivation of its tumor suppressive transcriptional activity. Several well-studied small molecular compounds are listed in the left part of this figure. The alternative approach is to targeting pathways that are critical for the survival and growth of p53-mutant cancers. Specific molecular targets, including G2/M regulators, kinases and are listed in the right part of this figure

Fig. 2

Strategies to target pathways induced by p53 GOF mutants. Mutant p53 gains new functions to promote tumorigenesis by activation of the metabolic melanovate pathway or upregulation of epigenetic enzymes. Drugs that target the melanovate pathway (simvastatin, GGTI-2133) or epigenetic enzymes (MLL1, MOZ inhibitors) show promise for the treatment of p53-mutant cancers. Cytoplasmic mutant p53 also promote tumor growth through activation of mTOR signaling, providing an opportunity to using mTOR inhibitors to treat cancers with cytoplasmic mutant p53. In addition, mutant p53 often gains novel function(s) to promote tumor invasion and metastasis through activation of cell invasion pathways (PDGFRβ signaling, RhoA/ROCK, EGFR/integrin recycling, Myo10, Pla2g16). Small molecular inhibitors (ROCK inhibitor, EGFR inhibitor, Myo10 inhibitor and Pla2g16 inhibitor) have been used to target each pathway to inhibit the metastatic ability of p53-mutant cancers