Fortifying p53 – beyond Mdm2 inhibitors

tumor suppressor p53 is mutated in roughly 50% of all human malignancies. However, in the other 50% of tumors which retain wildtype p53, it appears insufficiently active to confer tumor suppression, through cell cycle arrest or apoptosis. Much of this p53-inactivation occurs through the Mdm2 oncoprotein, the product of a p53-inducible gene. Mdm2 is an E3 ubiquitin-ligase that targets p53 for proteasomal degradation. In 2004, a small-molecule antagonist of Mdm2 was identified, known as Nutlin-3a or Nutlin. It binds to Mdm2 at the p53 binding pocket, thereby leading to activation of p53 and its target genes [2]. Recently, similar Mdm2 antagonists were taken to clinical trials, such as RG7388 (NCT01636479), but the results regarding their efficacy have not been reported so far. Thus, delivering a wake-up call to dormant p53 in tumors remains a tempting but currently not proven option for cancer therapy. While Nutlin readily induces cell cycle arrest, it was found ineffective in causing apoptosis in most tumor cells tested, even when p53 was wild type [3]. This raises the need to fortify the ability of Mdm2 antagonists to induce the pro-apoptotic functions of p53. In analogy to Mdm2, Wip1 (Wild-type p53 induced phosphatase, also known as PPM1D) is another p53-inducible antagonist to p53, often overexpressed in p53-wildtype cancer cells. Wip1 belongs to the PP2C family of Mg 2+ /Mn 2+-dependent serine/threonine phosphatases and causes the dephosphorylation of p53 at Ser 15, thereby reducing p53 activity. It also dephosphorylates Mdm2, resulting in even more efficient p53 inhibition [4]. In 2014, an allosteric inhibitor of Wip1 known as GSK 2830371 was identified. It binds to the structural flap domain of Wip1 and reduces tumor cell growth in lymphoma xenograft models, the breast cancer cell line MCF-7, and neuroblastoma cells [5]. In our study [1], we tested whether the simultaneous inhibition of both p53-antagonists, Mdm2 and Wip1, might induce p53 more potently than single inhibitors. And indeed, the combination of Nutlin and Wip1 inhibitor led to increased activity and stability of p53 that resulted in a major proportion of cells arresting at the G2/M phase of the cell cycle and/or undergoing Editorial senescence. Similar results were independently obtained by others [6, 7]. Thus, p53 activity can be fortified by the combined inhibition of factors that otherwise provide negative feedback on p53. This raises the perspective of interfering with p53-regulation at multiple levels (Fig. 1) to further boost p53 for cancer …