Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53

Abstract

Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ∼50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 "gain-of-resistance" phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild-type p53 cancers.

Fig. 1

Deregulation of pathways attenuating p53-dependent drug response.

Fig. 2

Cisplatin resistance in an ovarian tumor panel according to p53 status. The A2780 cell line is the sensitive tumor model. The resistant models are grouped into mutant (mu)/null p53 (N = 4) and wild-type p53 (N = 6); the 2780CP cell line was developed in tissue culture from A2780 cells, whereas all others were established directly from patients’ biopsies. The IC₅₀ value is the concentration of cisplatin that inhibits cell proliferation by 50% and is expressed as μM. Adapted from Hagopian et al. [40] and Siddik et al. [213].