PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

Rökaeus, Nina; Shen, Jun; Eckhardt, I; Bykov, Vladimir J.N.; Wiman, Klas G.; Wilhelm, Margareta

doi:10.1038/onc.2010.382

Cited by 54 publications

(53 citation statements)

References 44 publications

(47 reference statements)

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“…APR-246 has recently been tested in a phase I/II clinical trial in patients with hematological malignancies or hormone-refractory prostate cancer (21). Interestingly, we found that APR-246 can restore the proapoptotic function to mutant TAp63γ in tumor cells (22). This finding suggests that APR-246-mediated rescue of mutants of the p53 family members involves a conserved molecular mechanism because of the extensive structural homology in the DNA-binding domains among these proteins.…”

mentioning

confidence: 61%

“…Indeed, treatment with APR-246 resulted in significant rescue of morphology and gene expression in R304W and R204W keratinocytes during epidermal differentiation. We recently showed that APR-246 can restore DNA binding, target gene expression, and proapoptotic activity to mutant isoforms of TAp63γ in human tumor cells (22). As different isoforms of p63 may regulate distinct target genes, it can be envisaged that APR-246-mediated restoration of wildtype function to different isoforms of mutant p63 expressed in various cell types may result in distinct biological consequences.…”

Section: Discussionmentioning

confidence: 99%

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APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Shen

Bogaard

Kouwenhoven

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1 MET (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/ II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.

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mentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Shen

Bogaard

Kouwenhoven

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…APR-246 was recently tested in a phase I/II clinical trial. Furthermore, APR-246 has been shown to also target mutant forms of p73 and p63, an effect that is presumably caused by highly homologous structural elements among the three p53 family member proteins (22). Our study is unique in showing that APR-246 can partially restore the molecular circuitry downstream of p63, which was affected in embryonic lineage commitment of EEC patientderived cells.…”

Section: δNp63mentioning

confidence: 81%

“…2E). Because corneal epithelial commitment of iPSC appeared more efficient and much faster than epidermal fate, we employed this system for testing whether the small compound APR-246/PRIMA-1 MET , that was recently shown to restore p63-induced apoptosis in human tumor cells (22), could rescue corneal epithelial commitment of iPSC EEC . Thus, iPSC WT , iPSC R204W/+ , and iPSC R304W/+ cells were treated with APR-246 (20 μM) from day 3 to day 14 and corneal commitment was monitored at day 14.…”

Section: Impaired Corneal Differentiation Of Eec-ipsc Is Rescued By Amentioning

confidence: 99%

“…Whereas both mutations are found within the DNA-binding domain, R304W is located in the Zn-binding pocket that is thought to affect the direct binding of p63 to the DNA phosphate moiety, but R204W possibly causes more drastic conformational changes and misfolding of the p63 protein (5). As a matter of fact, Rökaeus et al, have also reported differential effects of APR-246 on the TAp63γR204W and TAp63γR304W mutants: APR-246 caused cell death in the presence of TAp63γR304W but induced mainly growth arrest in cells with TAp63γR204W (22). It would be interesting to investigate whether there is a difference between the binding of APR-246 to the two mutated p63 forms by in vitro assays.…”

Section: δNp63mentioning

confidence: 99%

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Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

Shalom-Feuerstein

Serror

Aberdam

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18 + cells but failed to further differentiate into K14 + cells (epidermis/limbus) or K3/K12 + cells (corneal epithelium). APR-246 (PRIMA-1 MET ), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.

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The TP73 complex network: Ready for clinical translation in cancer?

Soldevilla

Millán

Bonilla

et al. 2013

Genes Chromosomes & Cancer

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TP73 is a member of the TP53 family, whose deregulated expression has been reported in a wide variety of cancers and linked to patients' outcome. The fact that TP73 encodes a complex number of isoforms (TAp73 and ΔTAp73) with opposing functions and the cross-talk with other members of the family (TP53 and TP63) make it difficult to determine its clinical relevance. Here, we review the molecular mechanisms driving TAp73 and ΔTAp73 expression and how these variants inhibit or promote carcinogenesis. We also highlight the intricate interplay between TP53 family members. In addition, we comment on current pharmacological approaches targeting the TP73 pathway and those affecting the TAp73/ΔTAp73 ratio. Finally, we discuss the current data available in the literature that provide evidence on the role of TP73 variants in predicting prognosis. To date, most of the studies that evaluate the status levels of TP73 isoforms have been based on limited-size series. Despite this limitation, these publications highlight the correlation between high levels of the oncogenic forms and failure to respond to chemotherapy and/or shorter survival. Finally, we emphasize the need for studies to evaluate the significance of combining the deregulation of various members of the TP53 family in order to define patient outcome or their responsiveness to specific therapies.

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PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

Cited by 54 publications

References 44 publications

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET

The TP73 complex network: Ready for clinical translation in cancer?

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PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

Cited by 54 publications

References 44 publications

APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 MET

The TP73 complex network: Ready for clinical translation in cancer?

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APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

APR-246/PRIMA-1 ^MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 ^MET