Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma

Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we...

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Published in:Cold Spring Harbor molecular case studies Vol. 6; no. 4
Main Authors: Anderson, Ashley N, McClanahan, Danielle, Jacobs, James, Jeng, Sophia, Vigoda, Myles, Blucher, Aurora S, Zheng, Christina, Yoo, Yeon Jung, Hale, Carolyn, Ouyang, Xiaoming, Clayburgh, Daniel, Andersen, Peter, Tyner, Jeffrey W, Bar, Anna, Lucero, Olivia M, Leitenberger, Justin J, McWeeney, Shannon K, Kulesz-Martin, Molly
Format: Journal Article
Language:English
Published: United States 01.08.2020
Subjects:
Aged
Aged, 80 and over
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - pathology
Cell Survival - genetics
Disease Progression
Exome Sequencing - methods
Gene Expression - genetics
Gene Expression Regulation, Neoplastic - genetics
Genomics - methods
Humans
Male
Middle Aged
Mutation - genetics
Receptor, EphA6 - antagonists & inhibitors
Receptor, EphA6 - metabolism
Receptor, EphA7 - antagonists & inhibitors
Receptor, EphA7 - metabolism
Signal Transduction - genetics
Skin Neoplasms - genetics
Small Molecule Libraries - pharmacology
squamous cell carcinoma of the skin
ISSN:2373-2873, 2373-2873
Online Access:Get more information
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Summary:Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES). Aberrations in molecular pathways with evidence of potential drug targets were identified, including the Eph-ephrin and neutrophil degranulation signaling pathways. Using a screening panel of siRNAs, we identified EPHA6 and EPHA7 as targets within the Eph-ephrin pathway responsible for mitigating decreased cell viability. These studies form a plausible foundation for detecting biomarkers of high-risk progressive disease applicable in dermatopathology and for patient-specific therapeutic options for invasive/metastatic cSCC.
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ISSN:2373-2873
2373-2873
DOI:10.1101/mcs.a005439