IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma

Song, Dawei; Cismas, Sonia; Crudden, Caitrin; Trocmé, Eric; Worrall, Claire; Suleymanova, Naida; Lin, Tingting; Zheng, Huiyuan; Seregard, Stefan; Girnita, Ada

doi:10.1038/s41388-021-02111-x

Cited by 9 publications

(11 citation statements)

References 64 publications

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“…In cutaneous melanoma cell lines, Dinaciclib-induced apoptosis was dependent on p53 signaling and expression both in vitro and in vivo [61]. The good response observed in our study with CM2005.1, CRMM1, and CRMM2 could possibly be linked the low level of p53 expression recently demonstrated in these cell lines [62]. In cutaneous melanoma [61], the effects of Dinaciclib correlated neither with the presence of BRAS or NRAS mutations, nor with CDK2 levels.…”

Section: Discussionsupporting

confidence: 41%

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Nardou

Nicolas

Kuttler

et al. 2022

Cancers

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Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.

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Section: Discussionsupporting

confidence: 41%

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Nardou

Nicolas

Kuttler

et al. 2022

Cancers

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Section: Genome Instability and Mutationmentioning

confidence: 99%

“…This function of Mdm2 and p53 constitutes a potential mechanism for the regulation of IGF1R and cell growth. As an operational outcome to these studies, IGF1R was identified as a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma (117). The characterization of the mechanisms responsible for regulation of the IGF1 pathway by p53, as described above, led us to formulate an hypothesis aimed at offering a generalized paradigm for regulation of IGF1R expression by different tumor suppressors (69,113,118).…”

Section: Genome Instability and Mutationmentioning

confidence: 99%

Hallmarks of cancer: The insulin-like growth factors perspective

Werner

LeRoith

2022

Front. Oncol.

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The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.

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“…More recently, the therapeutic use of Nutlin-3 was showed in another disease of the conjunctiva, the conjunctival melanoma that typically express p53 in wild-type status. These authors demonstrated that Nutlin-3 was able to reactivate p53 and reduced viability in several models of conjunctival melanoma, both in vitro in cell lines and 3D spheroids, as well as in vivo in zebrafish xenografts ( 60 ). Considering the retina, an ocular formulation of Nutlin-3 was used in preclinical models of retinoblastoma, a pediatric disease characterized for expressing high levels of MDM2/HDMX ( 61 ).…”

Section: Modulation Of P53 Activity In Pathological Ocular Tissues Fo...mentioning

confidence: 99%

Therapeutic potential of the MDM2 inhibitor Nutlin-3 in counteracting SARS-CoV-2 infection of the eye through p53 activation

et al. 2022

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Starting from the beginning of the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) global pandemic, most of the published data has concentrated on the respiratory signs and symptoms of Covid-19 infection, underestimating the presence and importance of ocular manifestations, such as conjunctivitis, usually reported in SARS-CoV-2 infected patients. With the present review we intend to resume the ocular involvement in SARS-CoV-2 infection and the recent discoveries about the different cell types and tissues of the eye that can be directly infected by SARS-CoV-2 and propagate the infection. Moreover, reviewing literature data about p53 expression in normal and diseased eye tissues, we hypothesize that the pleiotropic protein p53 present at high levels in cornea, conjunctiva and tear film might play a protective role against SARS-CoV-2 infection. Since p53 can be easily up-regulated by using small molecule non-genotoxic inhibitors of MDM2, we propose that topical use of Nutlin-3, the prototype member of MDM2 inhibitors, might protect the anterior surface of the eye from SARS-CoV-2 infection, reducing the spreading of the virus.

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IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma

Cited by 9 publications

References 64 publications

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Hallmarks of cancer: The insulin-like growth factors perspective

Therapeutic potential of the MDM2 inhibitor Nutlin-3 in counteracting SARS-CoV-2 infection of the eye through p53 activation

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