The oncogene p53 is a key regulator of various cell death pathways such as apoptosis, necrosis, senescence, autophagy, and iron death, so it has been an important anti-cancer target. Previous p53-targeted therapies have mainly focused on inhibiting its E3-linked enzyme MDM2, thereby activating the p53 oncogenic pathway in tumor cells. Since the discovery of Nutlin, the first MDM2 small molecule inhibitor in 2004, various novel MDM2 inhibitors and clinical trials (including monotherapy and combination therapies) have emerged, yet none of them have been approved for marketing by the FDA.

To date, several clinical trials have confirmed that MDM2 inhibitors activate the p53 pathway in normal tissues as well, resulting in cell death and strong cytotoxicity, which is one of the biggest challenges for MDM2 inhibitors. Therefore, how to activate p53 in tumor cells while avoiding toxicity in normal tissues has become an urgent scientific question.

On April 7, 2023, Professor Wei Gu's research team at Columbia University published online in Nature Communications an article entitled "Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy". It was discovered for the first time that the deubiquitinating enzyme USP2 protein can regulate both p53 and PD-L1 signaling pathways through the downstream target VPRBP, and that the combination of USP2 small molecule inhibitors and PD-1/PD-L1 immune checkpoint inhibitors can completely inhibit tumor proliferation in multiple mouse tumor models without cytotoxicity in normal mouse tissues. This paper provides a novel idea to solve the cytotoxicity challenges of p53-targeted therapies.

First, USP2 can regulate two key cancer targets, p53 and PD-L1, simultaneously. In terms of molecular mechanism, this paper reports for the first time that VPRBP is a new target of USP2 deubiquitinating enzyme. Several papers had demonstrated that VPRBP could promote ubiquitination and degradation of p53 protein, and also directly or indirectly inhibit p53 transcriptional activity. Therefore, VPRBP is one of the key regulatory proteins of p53, which is no less important than MDM2.

Second, combination therapy with the USP2 inhibitor ML364 and PD-1/PD-L1 immune checkpoint inhibitors was effective in a variety of murine p53 wild-type tumor models.

Third, the combination therapy did not produce significant toxicity to normal tissues. the main toxicity produced by the MDM2 inhibitor was inhibition of hematopoiesis in the bone marrow due to cell death induced by p53 activation. Gu Wei's team examined whole blood and bone marrow from mice treated with the USP2 inhibitor ML364 and showed no significant cytotoxicity.

To top it all off, the combination therapy did not have a significant negative impact on the normal tissues. The main negative impact of the MDM2 inhibitor was its inhibition of bone marrow hematopoiesis due to cell death brought on by p53 activation. Researchers found no evidence of cytotoxicity in analyses of whole blood and bone marrow from mice treated with the USP2 inhibitor ML364.

These findings prompted a unique approach to overcoming the problem of cytotoxicity in p53-targeted drugs.