First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models

Pairawan, Seyed; Zhao, Ming; Yuca, Erkan; Annis, Allen; Evans, Kurt W.; Sutton, David; Carvajal, Luis A.; Ren, Junyu; Santiago, Solimar; Guerlavais, Vincent; Akçakanat, Argun; Tapia, Coya; Yang, Fei; Bose, P.; Zheng, Xiaofeng; Dumbrava, Ecaterina Ileana; Aivado, Manuel; Meric‐Bernstam, Funda

doi:10.1186/s13058-021-01406-x

Cited by 37 publications

(39 citation statements)

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“…While nutlins can strongly activate wtp53 in tumors overexpressing MDM2, they are unable to activate the p53 pathway in cancers overexpressing MDMX due to subtle differences in the N-terminal p53-binding pocket of MDMX [ 39 ]. ALRN-6924 was the only dual MDM2 and MDMX inhibitor to reach clinical trials after preclinical investigations revealed a considerable antitumor effect [ 40 , 41 ]. Since MDM2 and MDMX have distinct anti-p53 activities, dual antagonists targeting both p53-MDM2 and p53-MDMX may have a greater effect than inhibiting either pathway alone.…”

Section: Targeting P53 For Cancer Therapymentioning

confidence: 99%

Targeting mutant p53 for cancer therapy: direct and indirect strategies

et al. 2021

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TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

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Section: Targeting P53 For Cancer Therapymentioning

confidence: 99%

Targeting mutant p53 for cancer therapy: direct and indirect strategies

et al. 2021

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“…Efforts to apply p53/MDM2-targeting therapeutic peptides for cancer treatment culminated in the development of a p53-derived stapled peptide, ALRN-6924. ALRN-6924 exhibits dual MDM2/MDMX inhibitory activities and has shown promise in preclinical studies and early-stage clinical trials to halt progression of cancers bearing WT p53 (Carvajal et al, 2018;Pairawan et al, 2021;Saleh et al, 2021). A recent study showed that ALRN-6924 induces inflammatory response in melanoma to alter TME and overcome tumor immune evasion, suggesting its potential utility in combination with immunotherapy (Zhou et al, 2021a).…”

Section: Therapeutic Peptides For P53 Activationmentioning

confidence: 99%

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

Kung

Weber

2022

Front. Cell Dev. Biol.

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Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the direction of p53 research, as well as the development of p53-based therapeutic strategies for the last 30 years. Our increasing knowledge of this triangle during this time, especially through identification of p53-independent functions of MDM2 and ARF, have uncovered many under-appreciated molecular mechanisms connecting these three proteins. Through recognizing both antagonizing and synergizing relationships among them, our consideration for harnessing these relationships to develop effective cancer therapies needs an update accordingly. In this review, we will re-visit the conventional wisdom regarding p53-MDM2-ARF tumor-regulating mechanisms, highlight impactful studies contributing to the modern look of their relationships, and summarize ongoing efforts to target this pathway for effective cancer treatments. A refreshed appreciation of p53-MDM2-ARF network can bring innovative approaches to develop new generations of genetically-informed and clinically-effective cancer therapies.

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“…Further study may identify context-independent elements of the p53 regulatory network that are needed for apoptosis or may reveal context-specific p53 responses that may be modulated or enhanced with combination treatments. This may involve dual treatment with multiple DNA-damaging agents which have the cumulative desired p53-dependent effect in the tissue of interest or may involve combination of DNA-damaging agents with p53-modulating compounds which show promising synergy in preclinical studies [ 23 , 24 , 25 , 26 , 27 ].…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

“…Furthermore, wild-type p53 function predicts better outcomes after treatment with conventional chemotherapy or radiation in a majority of clinical studies [ 22 ]. Moreover, p53 activation can synergize with DNA-damaging agents to kill cancer cells [ 23 , 24 , 25 , 26 , 27 ]. Several p53-activating or -reactivating compounds are in various stages of clinical trials [ 28 ], but currently there are no FDA-approved therapies that target either wild-type or mutant p53.…”

Section: Introductionmentioning

confidence: 99%

Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents

Carlsen

El‐Deiry

2021

IJMS

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The gene TP53, which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics.

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First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models

Cited by 37 publications

References 50 publications

Targeting mutant p53 for cancer therapy: direct and indirect strategies

Targeting mutant p53 for cancer therapy: direct and indirect strategies

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents

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