Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

Hároníková, Lucia; Bonczek, Ondřej; Zatloukalová, Pavlína; Kokas-Zavadil, Filip; Kucerikova, Martina; Coates, Philip J.; Fåhræus, Robin; Vojtesek, Borek

doi:10.1186/s11658-021-00293-6

Cited by 29 publications

(23 citation statements)

References 242 publications

(318 reference statements)

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“…The first clinically tested molecule is RG7112 (IC50 ~20 nM), a new member of the nutlin family ( 20 , 22 , 23 ). Furthermore, idasanutlin, a second-generation molecule (RG7388, IC50 ~6 nM), possesses better pharmacokinetic properties, enhanced potency, better selectivity, and enhanced bioavailability compared to the first-generation nutlins and RG7112.…”

Section: Mdm2 Inhibitorsmentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.

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Section: Mdm2 Inhibitorsmentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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“…The wild-type p53-PUMA pathway was found to have the potential to drive the metabolic switch of cancer cells, and wild-type p53 is required for the maintenance of cancer cell growth and glycolysis in several cancers [ 93 ], indicating that activation of p53 in some cases may have the opposite effect, which was consistent with results from other studies [ 94 – 96 ]. MDM2 inhibitors may promote the emergence of p53 mutations and lead to genomic instability through a p53-independent mechanism, resulting in acquired resistance against MDM2 inhibitors [ 97 – 99 ]. In addition, although missense mutations in MDM2 are rare, multiple isoforms of MDM2 protein generated by alternative promoters and alternative proteins have been observed, and the change in the sequence may disrupt the N-terminal p53-binding domain to reduce the efficacy of MDM2 inhibitors and promote tumor progression [ 100 – 103 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

Zhu

Gao

et al. 2022

J Hematol Oncol

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Abstractp53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction.

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“…However, specific clinical trials targeting MDM2 in kidney cancer have to still be planned. Conversely, different clinical trials in solid tumors and hematologic neoplasms by using MDM2 inhibitors, such as RG7112, idasanutlin, APG-115, and ALRN-6924, have already completed phase-1 trials [ 58 , 59 ]. Most of these seem well tolerated except for RG7112, which shows different side effects.…”

Section: Current and New Targeted Therapies For Rcc Treatmentmentioning

confidence: 99%

“…Most of these seem well tolerated except for RG7112, which shows different side effects. Nevertheless, some MDM2 inhibitors show ineffectiveness, while clinical trials testing other MDM2 antagonists are currently in progress [ 58 ].…”

Section: Current and New Targeted Therapies For Rcc Treatmentmentioning

confidence: 99%

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

Dell’Atti

Bianchi

Aguiari

2022

Cancers

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Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC.

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Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

Cited by 29 publications

References 242 publications

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

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