Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients

Hassin, Ori; Nataraj, Nishanth Belugali; Shreberk-Shaked, Michal; Aylon, Yael; Yaeger, Rona; Fontemaggi, Giulia; Mukherjee, Saptaparna; Maddalena, Martino; Avioz, Adi; Iancu, Ortal; Mallel, Giuseppe; Gershoni, Anat; Grosheva, Inna; Feldmesser, Ester; Ben-Dor, Shifra; Golani, Ofra; Hendel, Ayal; Blandino, Giovanni; Kelsen, David P.; Yarden, Yosef; Oren, Moshe

doi:10.1038/s41467-022-30481-7

Cited by 40 publications

(21 citation statements)

References 78 publications

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“…Although abrogation of mutp53 GOF via its targeted elimination remains a sensible approach, it may lose its appeal with the emergence of better drugs that restore the functionality of mutp53, thereby reconstituting tumour suppressor activities while at the same time abrogating inherent mutp53 GOF. Moreover, as the GOF effects of mutp53 are often context dependent and vary between various types of p53 mutant 120 – 123 , further elucidation of those effects may be required to stratify cancer patients for mutp53-directed treatments.…”

Section: Small Moleculesmentioning

confidence: 99%

Drugging p53 in cancer: one protein, many targets

Hassin

Oren

2022

Nat Rev Drug Discov

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317

181

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Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.

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Section: Small Moleculesmentioning

confidence: 99%

Drugging p53 in cancer: one protein, many targets

Hassin

Oren

2022

Nat Rev Drug Discov

Self Cite

317

181

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“…Another promising gene therapy technology uses small-interfering RNAs (siRNAs) to target p53 mRNA and block protein production (Figure D). The understanding that p53 mutations behave differently and carry different phenotypes brings the urgent need for personalized medicine focusing on target selectivity and avoiding a generalist drug. Ubby and colleagues developed a series of mutant-p53-specific siRNAs (MupSi-p53) targeting four hotspot p53 mutations that revealed high specificity to knock down the expression of the desired mutation and has not interfered with the wt p53 expression levels .…”

Section: Strategies To Target Misfolded P53 Mutant P53 Aggregation An...mentioning

confidence: 99%

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

et al. 2023

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Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

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“…Consistently, TP53 -mutation bearing tumors tend to be more resistant to various cancer chemotherapies (4, 9–11) and radiotherapy ( 10–12 ), and more aggressive i.e. TP53 R273 and R248 mutants are associated with accelerated cancer progression in colorectal tumors (13).…”

Section: Introductionmentioning

confidence: 95%

Prevalence, causes and impact ofTP53-loss phenocopying events in human tumors

Fito-Lopez

Salvadores

Álvarez

et al. 2022

Preprint

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TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity -- which may occur from trans-acting alterations -- from gene expression patterns. We apply this approach to transcriptomes of ~8,000 tumors and ~1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, others are not. An analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and are comparable to MDM4 amplifications in terms of effect size. Additionally, in the known CNA segments harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect. An analysis using the phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and relevant genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a relevant interacting factor in personalized medicine studies. As a resource, we provide the drug-marker associations that differ depending on TP53 functional status.

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Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients

Cited by 40 publications

References 78 publications

Drugging p53 in cancer: one protein, many targets

Drugging p53 in cancer: one protein, many targets

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Prevalence, causes and impact ofTP53-loss phenocopying events in human tumors

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