The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

• Klíčová slova
• combination therapy, integrated stress response, nelfinavir, nutlin, p53, polytherapy,
• MeSH
• cílená molekulární terapie * MeSH
• lidé MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   antagonisté a inhibitory   MeSH
• nádory * farmakoterapie   metabolismus   genetika   MeSH
• protinádorové látky * terapeutické užití   farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorový supresorový protein p53 * MeSH
• protinádorové látky * MeSH
• protoonkogenní proteiny c-mdm2 MeSH

BACKGROUND: PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood. METHODS: The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients. RESULTS: We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis. CONCLUSIONS: We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response.

• Klíčová slova
• IFNγ, IRF1, PD-L1, SOX10, p53,
• MeSH
• antigeny CD274 * metabolismus   genetika   MeSH
• buňky NK metabolismus   imunologie   MeSH
• interferon gama metabolismus   genetika   MeSH
• interferonový regulační faktor 1 * metabolismus   genetika   MeSH
• lidé MeSH
• melanom * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce * MeSH
• transkripční faktory SOXE * metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 * MeSH
• CD274 protein, human MeSH Prohlížeč
• interferon gama MeSH
• interferonový regulační faktor 1 * MeSH
• IRF1 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 * MeSH
• SOX10 protein, human MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč
• transkripční faktory SOXE * MeSH

Activation of p53 by small molecule MDM2 inhibitors can induce cell cycle arrest or death in p53 wildtype cancer cells. However, cancer cells exposed to hypoxia can develop resistance to other small molecules, such as chemotherapies, that activate p53. Here, we evaluated whether hypoxia could render cancer cells insensitive to two MDM2 inhibitors with different potencies, nutlin-3a and navtemadlin. Inhibitor efficacy and potency were evaluated under short-term hypoxic conditions in human and mouse cancer cells expressing different p53 genotypes (wild-type, mutant, or null). Treatment of wild-type p53 cancer cells with MDM2 inhibitors reduced cell growth by > 75% in hypoxia through activation of the p53-p21 signaling pathway; no inhibitor-induced growth reduction was observed in hypoxic mutant or null p53 cells except at very high concentrations. The concentration of inhibitors needed to induce the maximal p53 response was not significantly different in hypoxia compared to normoxia. However, inhibitor efficacy varied by species and by cell line, with stronger effects at lower concentrations observed in human cell lines than in mouse cell lines grown as 2D and 3D cultures. Together, these results indicate that MDM2 inhibitors retain efficacy in hypoxia, suggesting they could be useful for targeting acutely hypoxic cancer cells.

• MeSH
• apoptóza MeSH
• hypoxie genetika   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory * farmakoterapie   genetika   MeSH
• protinádorové látky * farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• nutlin 3 MeSH Prohlížeč
• protinádorové látky * MeSH
• protoonkogenní proteiny c-mdm2 MeSH