p53 as an Effector or Inhibitor of Therapy Response

Abstract

Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors.

Figure 1.

Expression of oncogenic RAS elicits PML nuclear body (NB) formation that subsequently triggers p53-mediated senescence. In contrast, PML/RARA prevents oncogenic stress-induced senescence by sequestering PML and disrupting NBs, thus obliterating p53 response.

Figure 2.

Arsenic treatment of acute promyelocytic leukemia (APL) induces PML/RARA degradation by direct binding and oxidation, followed by SUMOylation and RNF4-dependent polyubiquitination. Retinoic acid (RA) targets the RARA part of PML/RARA and initiates its proteasome-dependent degradation. Loss of PML-RARA passive reformation of PML nuclear bodies (NBs). The latter is also enhanced by arsenic through its direct binding onto normal PML. Acute NB reformation triggers p53 activation, presumably via p53-modifying enzymes that reside in NBs, which initiates the senescence of APL cells and results in definitive disease elimination.

Figure 3.

High-dose DNA-damaging chemotherapy showed significant clinical benefit in mutant p53 compared with wild-type p53 breast cancer patients. In cells with active p53 signaling, DNA damage induces senescence of cancer cells, which protects tumor-propagating cells from eradication. In contrast, in cells with nonfunctional p53, dose-dense chemotherapy triggers mitotic catastrophe and eliminates tumor-propagating cells, yielding long-lasting complete remissions.