The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH activating agents capable to restore its tumour-suppressor function.
The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH activating agents capable to restore its tumour-suppressor function.
In this study, we aim to compare the incidence of BCC and cuSCC in patients with metastatic melanoma treated with antiprogrammed cell death-1 (anti-PD1), BRAF inhibitor (BRAFi) monotherapy or dabrafenib and trametinib combination therapy (CombiDT) with a group of control patients having similar risk factors.
More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses.
Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs.
In response to miR-154 mimic or siRNA-WHSC1, SCC A431 and SCC-15 cell lines exhibited increased expression of P73, P16 and Bax, decreased expression of WHSC1, P53, c-myc and Bcl-2, as well as attenuated cell viability and enhanced cell apoptosis.
We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development.
Sections of formalin fixed paraffin-embedded tumor tissue from 54 cases of Morbus Bowen (preinvasive cutaneous carcinoma) and 41 cases of invasive squamous cell carcinoma of the skin were subjected to HPV genotyping using Lipa (Line imuno probe assay), immunohistochemical staining for p16(INK4A), p53, pRb and prepared for flow cytometry DNA content analysis.
Recently, Human Polyomavirus 6 (HPyV6) was found to actively express viral proteins in BRAF inhibitor-induced cSCCs; however, the specific cellular mechanisms by which HPyV6 may facilitate neoplastic cell growth require further investigation.
BRAF inhibitor-associated cutaneous squamous cell carcinoma: new mechanistic insight, emerging evidence for viral involvement and perspectives on clinical management.
The use of single agent BRAF inhibitor significantly increased the risk of developing cuSCC comparing with dual BRAF/MEK inhibitors for all-grade (RR 4.72, 95% CI: 2.42-9.20) and high-grade (RR 4.92, 95% CI: 2.64-9.16) in cancer patients.
Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation.
The presence of wild type p53 (seborrheic keratosis) or mutant p53 (cutaneous squamous cell carcinoma) appears to dictate whether a lesion is sensitive to Akt inhibition or not.
Treatment with vemurafenib, and to a lesser extent, sorafenib, a relatively non-specific inhibitor of BRAF, has been associated with cutaneous squamous cell carcinoma (SCC).
Here, we summarize our current knowledge about the biological activities of p53 family members in cSCC and propose that integration of their signalling with Notch is key to cSCC formation and progression.