Topical kinase inhibitors induce regression of cutaneous squamous cell carcinoma

Yang, Xiao‐Ping; Daifallah, Aliaa E. M.; Shankar, Shiela; Beer, Jacob; Marshall, Christine; Dentchev, Tzvete; Seykora, Francesca; D'Armas, Sebastian; Hahn, Jaeyi; Lee, Vivian; Sabry, H.H.; Farag, Ahmed; Seykora, John T.

doi:10.1111/exd.13902

Cited by 12 publications

(17 citation statements)

References 15 publications

(16 reference statements)

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“…They found increased levels of phosphorylated PDK1, together with STAT3 and ERK1/2, in both precancerous and SCCs lesions, compared with nonlesional epidermis. Of note, topical application of BEZ-235, a PI3K/mTOR inhibitor, induces regression of SCC in this disease model (77).…”

Section: Role Of Pi3k/akt/mtor Pathway In Growth and Proliferation In Nmscmentioning

confidence: 76%

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

2021

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PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

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Section: Role Of Pi3k/akt/mtor Pathway In Growth and Proliferation In Nmscmentioning

confidence: 76%

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

2021

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“…In orthotopic mouse xenograft models, dasatinib treatment was shown to cause prominent inhibition of tumour growth through interference with SFK-induced YAP nuclear translocation and activation [121]. Of note, topical dasatinib application was recently found to induce regression of murine cSCC with less inflammation, no ulceration and no mortality compared to treatment with 5-fluorouracil, one of the standard chemotherapies for cSCC [200]. SFK inhibition-induced suppression of YAP/TAZ activity might also be beneficial for the treatment of metastatic melanoma [129].…”

Section: Targeting Yap and Taz For Skin Cancer Treatmentmentioning

confidence: 99%

The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin

Rognoni

Walko

2019

Cells

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Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss the current knowledge of how the Hippo pathway and its downstream effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) contribute to the maintenance, activation and coordination of the epidermal and dermal cell populations during development, homeostasis, wound healing and cancer.

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“…Topical Vcz also enhanced UV‐induced epithelial hyperproliferation, Src kinase activity, and DNA damage as indicated by higher nuclear p53BP1 (Figure C‐H). Since Vcz activates Src kinases in UV‐treated keratinocytes, one potential approach to preventing Vcz‐induced cSCCs could be to apply topical tyrosine kinase inhibitors to sun‐exposed skin …”

Section: Discussionmentioning

confidence: 99%

Voriconazole enhances UV‐induced DNA damage by inhibiting catalase and promoting oxidative stress

Lee

Gober

Bashir

et al. 2019

Experimental Dermatology

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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and is associated with cumulative UV exposure. Studies have shown that prolonged voriconazole use promotes cSCC formation; however, the biological mechanisms responsible for the increased incidence remain unclear. Here, we show that voriconazole directly increases oxidative stress in human keratinocytes and promotes UV‐induced DNA damage as determined by comet assay, 8‐oxoguanine immunofluorescence and mass spectrometry. Voriconazole treatment of human keratinocytes potentiates UV‐induced apoptosis and activation of the p38 MAP kinase and 53BP1 UV stress response pathways. The p38 MAP kinase activation promoted by voriconazole exposure can be mitigated by pretreating keratinocytes with N‐acetylcysteine. Voriconazole increases oxidative stress in keratinocytes by directly inhibiting catalase leading to lower intracellular NADPH levels and the triazole moieties in voriconazole are critical for inhibiting catalase. Furthermore, voriconazole is shown to promote UV‐induced dysplasia in an in vivo model. Together, these data demonstrate that voriconazole potentiates oxidative stress in UV‐irradiated keratinocytes through catalase inhibition. Use of antioxidants may mitigate the pro‐oncogenic effects of voriconazole.

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Topical kinase inhibitors induce regression of cutaneous squamous cell carcinoma

Cited by 12 publications

References 15 publications

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin

Voriconazole enhances UV‐induced DNA damage by inhibiting catalase and promoting oxidative stress

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