WIP1 phosphatase as pharmacological target in cancer therapy

Abstract

DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

Keywords: Cancer; Checkpoint; DNA damage response; Inhibitor; Phosphatase; p53.

Fig. 1

Role of WIP1 phosphatase in termination of DNA damage response. Exposed ssDNA caused by stalled replication forks or resected DSBs activates ATR/CHK1 pathway that targets CDC25 family of phosphatases, prevents activation of CDKs, and triggers cell cycle arrest. DSBs induced by ionizing radiation or chemotherapy activate ATM that orchestrates DNA repair by phosphorylating histone H2AX at chromatin and activates the cell cycle checkpoint. This is achieved by phosphorylation of p53 and Mdm2 that allows stabilization of p53 and triggers expression of CDKN1/p21. In addition, p53 stimulates expression of its negative regulators Mdm2 and WIP1. After accumulating sufficient protein levels, WIP1 inactivates p53 pathway and dephosphorylates other targets jointly contributing to termination of the DDR (negatively and positively regulated WIP1 substrates shown in blue and yellow, respectively). Persistent genotoxic stress can continuously activate p53 leading to senescence. Very high activation of p53 pathway leads to expression of PUMA and NOXA and leads to cell death

Fig. 2

Amplification of PPM1D locus in breast cancer. Breast invasive carcinoma dataset (n = 817, [48]) was analyzed for PPM1D amplification (11%), TP53 mutation (31%), and ERBB2 amplification, overexpression, or mutation (18%) using cBioPortal [49]. Amplification of genes was analyzed using putative copy number alterations from GISTIC. Expression analysis was based on mRNA Expression z scores (RNA Seq V2 RSEM) where threshold was set at fourfold difference. Tendency to mutual exclusivity between PPM1D and TP53 mutation as well as tendency to co-occurrence between PPM1D and ERBB2 activation were statistically significant

Fig. 3

Model for WIP1 involvement in tumorigenesis and in therapeutic response. Activation of oncogenes (such as RAS and MYC) causes replication stress, stimulates p53 activity, and results in permanent cell cycle arrest called oncogene-induced senescence (OIS). Inactivating mutation of TP53, overexpression of WIP1, or amplification of PPM1D leads to suppression of p53 pathway, disables establishment of OIS, and promotes tumor formation. Inhibition of WIP1 does not affect proliferation of cancer cells with mutant TP53 whereas it allows partial reactivation of p53 pathway in cells with wild-type TP53 slowing down their proliferation. Combination of WIP1 inhibition with MDM2 antagonist nutlin-3 or with DNA damage-inducing chemotherapy allows maximal activation of p53 pathway leading to induction of cell death or senescence and preventing tumor growth