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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| Veröffentlicht in: | Cold Spring Harbor molecular case studies Jg. 6; H. 4 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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01.08.2020
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| ISSN: | 2373-2873, 2373-2873 |
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| Abstract | 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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| AbstractList | 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.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. 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. |
| Author | Andersen, Peter Anderson, Ashley N Hale, Carolyn Zheng, Christina Jeng, Sophia Leitenberger, Justin J Vigoda, Myles McWeeney, Shannon K Kulesz-Martin, Molly Blucher, Aurora S Yoo, Yeon Jung Lucero, Olivia M Bar, Anna McClanahan, Danielle Ouyang, Xiaoming Jacobs, James Clayburgh, Daniel Tyner, Jeffrey W |
| Author_xml | – sequence: 1 givenname: Ashley N orcidid: 0000-0002-7522-846X surname: Anderson fullname: Anderson, Ashley N organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 2 givenname: Danielle surname: McClanahan fullname: McClanahan, Danielle organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 3 givenname: James surname: Jacobs fullname: Jacobs, James organization: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA – sequence: 4 givenname: Sophia surname: Jeng fullname: Jeng, Sophia organization: Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon 97339, USA – sequence: 5 givenname: Myles surname: Vigoda fullname: Vigoda, Myles organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 6 givenname: Aurora S orcidid: 0000-0001-6460-010X surname: Blucher fullname: Blucher, Aurora S organization: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA – sequence: 7 givenname: Christina surname: Zheng fullname: Zheng, Christina organization: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA – sequence: 8 givenname: Yeon Jung surname: Yoo fullname: Yoo, Yeon Jung organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 9 givenname: Carolyn surname: Hale fullname: Hale, Carolyn organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 10 givenname: Xiaoming orcidid: 0000-0002-6632-3190 surname: Ouyang fullname: Ouyang, Xiaoming organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 11 givenname: Daniel surname: Clayburgh fullname: Clayburgh, Daniel organization: Operative Care Division, Veterans Affairs Medical Center, Portland, Oregon 97239, USA – sequence: 12 givenname: Peter surname: Andersen fullname: Andersen, Peter organization: Department of Otolaryngology, Oregon Health & Science University, Portland, Oregon 97239, USA – sequence: 13 givenname: Jeffrey W orcidid: 0000-0002-2133-0960 surname: Tyner fullname: Tyner, Jeffrey W organization: Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA – sequence: 14 givenname: Anna surname: Bar fullname: Bar, Anna organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 15 givenname: Olivia M surname: Lucero fullname: Lucero, Olivia M organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 16 givenname: Justin J surname: Leitenberger fullname: Leitenberger, Justin J organization: Department of Dermatology, Oregon Health and Science University, Portland, Oregon 97239, USA – sequence: 17 givenname: Shannon K orcidid: 0000-0001-8333-6607 surname: McWeeney fullname: McWeeney, Shannon K organization: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA – sequence: 18 givenname: Molly orcidid: 0000-0001-7642-4051 surname: Kulesz-Martin fullname: Kulesz-Martin, Molly organization: Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA |
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| Copyright | 2020 Anderson et al.; Published by Cold Spring Harbor Laboratory Press. |
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| Snippet | Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are... |
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| SubjectTerms | 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 |
| Title | Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma |
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