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Combined VEGFR and MAPK Pathway Inhibition in Angiosarcoma Michael J

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Combined VEGFR and MAPK Pathway Inhibition in Angiosarcoma Michael J www.nature.com/scientificreports OPEN Combined VEGFR and MAPK pathway inhibition in angiosarcoma Michael J. Wagner1,2*, Yasmin A. Lyons3, Jean H. Siedel3, Robert Dood3, Archana S. Nagaraja3, Monika Haemmerle3,8, Lingegowda S. Mangala3, Pritha Chanana4, Alexander J. Lazar5,9, Wei‑Lien Wang5, Vinod Ravi6, Eric C. Holland7 & Anil K. Sood3 Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen‑activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin‑fxed parafn embedded tissue archival samples were stained for phospho‑ extracellular signal‑regulated kinase (p‑ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen‑activated protein kinase kinase (MEK) inhibitor trametinib, pan‑VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression efects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive efect in in vitro models, and a combinatorial efect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA‑ seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted. Abbreviations BRAF B-Raf proto-oncogene DUSP Dual specifcity protein phosphatase DMEM Dulbecco’s modifed eagle medium EGR1 Early growth response 1 ETV5 ETS variant transcription factor 5 FCGBP Fc fragment of IgG binding protein FGFR2 Fibroblast growth factor receptor 2 FLT4 FMS related receptor tyrosine kinase 4 GSEA Gene set enrichment analysis HRAS H-Ras Proto-Oncogene ITGA6 Integrin subunit alpha 6 IL2 Interleukin 2 1Division of Medical Oncology, University of Washington, 825 Eastlake Ave E, Seattle, WA 98109, USA. 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA. 3Department of Gynecologic Oncology and Reproductive Medicine and Center for RNA Interference and Non-Coding RNA, UT MD Anderson Cancer Center, Houston, USA. 4Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, USA. 5Department of Pathology, UT MD Anderson Cancer Center, Houston, USA. 6Sarcoma Medical Oncology, UT MD Anderson Cancer Center, Houston, USA. 7Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, USA. 8Present address: Section for Experimental Pathology, Medical Faculty, Institute of Pathology, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. 9Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, USA. *email: [email protected] Scientifc Reports | (2021) 11:9362 | https://doi.org/10.1038/s41598-021-88703-9 1 Vol.:(0123456789) www.nature.com/scientificreports/ IL4 Interleukin 4 IL7 Interleukin 7 KRT Keratin KDR Kinase insert domain receptor KRAS K-Ras proto-oncogene LGR4 Leucine-rich repeat-containing G-protein coupled receptor 4 mTOR Mechanistic target of rapamycin MAPK Mitogen-activated protein kinase MAPK1 Mitogen-activated protein kinase 1 MEK Mitogen-activated protein kinase kinase MYC Myc proto-oncogene NF1 Neurofbromin 1 NRAS N-Ras proto-oncogene p-ERK Phospho-extracellular signal-regulated kinase PI3K Phosphoinositide-3-Kinase PLCG1 Phospholipase C gamma 1 PCA Principal component analysis PCDH19 Protocadherin 19 AKT Protein kinase B CRAF Raf-1 proto-oncogene RPPA Reverse phase protein array SERTAD4 SERTA domain-containing protein 4 VEGFR Vascular endothelial growth factor Angiosarcoma is a rare malignancy of endothelial cells, with an incidence of 400–500 new cases per year in the United States. Tey are aggressive tumors with a high propensity to spread. Five year survival for all patients, including those presenting with localized disease is less than 50%, and median overall survival for patients with metastatic disease is eight months 1. Terefore, new treatment approaches are needed. Initial eforts to identify drivers of angiosarcoma have revealed several recurrent aberrations in angiogenesis pathways2,3. Tese include activating mutations in kinase insert domain receptor (KDR) and phospholipase C gamma 1 (PLCG1), and loss of function mutation in receptor-type tyrosine-protein phosphatase beta (PTPRB)4,5. Secondary angiosarcomas (e.g., radiation and lymphedema induced) are characterized by Myc proto-oncogene (MYC) amplifcation and a subset also have FMS related receptor tyrosine kinase 4 (FLT4) amplifcation6. Tis greater understanding of driver mutations in angiosarcoma yields insights into potential targets for clinical care. Some analyses have suggested alterations in pathways downstream from vascular endothelial growth factor receptor 2 (VEGFR2) are relevant targets for angiosarcoma, focusing largely on the Phosphoinositide-3-Kinase (PI3K)/ mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways. In particular, MAPK pathway alterations have been identifed in angiosarcoma clinical samples with mutations in K-Ras Proto-Oncogene (KRAS), H-Ras Proto-Oncogene (HRAS), N-Ras Proto-Oncogene (NRAS), B-Raf Proto-Oncogene (BRAF), Raf-1 Proto-Oncogene (CRAF), mitogen-activated protein kinase 1 (MAPK1) and Neurofbromin 1 (NF1)7. Te recurrent R707Q mutation in PLCG1 leads to canonical activation of the MAPK pathway8 and leads to acquired resistance to VEGFR inhibition 9. In spite of these potentially targetable mutations, targeted agents modulating angiogenesis pathways in angio- sarcoma clinical studies have overall been disappointing with response rates less than 20%10–12. One potential strategy to overcome this intrinsic resistance is to concurrently target multiple parallel signaling pathways. Indeed, dual inhibition of mTOR and MEK has been shown to be efcacious in a mouse model of angiosarcoma 13. We sought to further investigate the potential for targeting the MAPK pathway in angiosarcoma with dual inhibi- tion of the VEGFR-MAPK axis. Materials and methods Cell lines and cell culture. SVR cells were obtained from ATCC and were maintained in Dulbecco’s Modi- fed Eagle Medium (DMEM) + 5% FBS + 0.1% gentamicin sulfate (Gemini Bioproducts, Calabasas, CA). ASM-1 angiosarcoma cells were generously provided by Dr. James Kirkpatrick (Johannes Gutenberg-Universität Mainz, Germany)14. HAMON angiosarcoma cells were generously provided by Dr. Riichiro Abe (Hokkaido University, Japan)15. ASM-1 and HAMON cells were maintained in EGM-2 endothelial cell growth media (Lonza). All cells were screened for mycoplasma and experiments were performed at 60–80% confuence. Drugs. Cediranib, a VEGFR inhibitor, and trametinib, a MEK inhibitor, were obtained from Selleckchem. Tey were reconstituted in DMSO and aliquots were stored at -20 degrees Celsius until use. Immunohistochemistry. Unstained slide was prepared from a tissue microarray consisting of sixty-nine clinical formalin-fxed parafn-embedded archival angiosarcoma specimens. IHC was performed on a Leica BOND RX automated IHC stainer (Lecia Biosystems, Bufalo Groove, IL). Te slide was baked at 60 °C, dewaxed with Bond dewax solution at 72 °C, rinsed in 100% EtOH, and Bond washed. Citrate bufer was used for epitope retrieval at 100 °C. Slides were blocked with hydrogen peroxide (3.0% H 2O2) for ten minutes and then with pro- tein block. Primary antibody against phospho-ERK (p44/42 MAPK 1:150 dilution, Cell Signaling Cat # 4370), the active form of ERK, was applied for 15 min at room temperature. Polymer enhanced secondary antibody Poly-HRP anti-rabbit IgG was applied for eight minutes. Labeling was assessed for degree of nuclear inten- Scientifc Reports | (2021) 11:9362 | https://doi.org/10.1038/s41598-021-88703-9 2 Vol:.(1234567890) www.nature.com/scientificreports/ sity (weak, moderate or strong) and extent of labeling (0, 0%; 1 + , 5%; 2 + , 6–25%; 3 + , 26–50%; 4 + , 51–75%; 5 + , > 75%). Specimens were labeled as being positive phospho-ERK when having at least 2 + tumoral labeling extent of any intensity. Focal labeling was defned as 1 + extent of any intensity. Clinical annotation for survival status was performed. Viability assays. SVR, HAMON, or ASM-1 cells were seeded in a 96 well plate at 5000 cells per well. Cells were grown overnight to 60–80% confuence and drugs were added the next day. Viability was assessed via standard MTT assay as previously described 16. Viability was assessed at 96 h for SVR cells and 7 days for HAMON and ASM-1 cells (2 doubling times). Media and drug were changed afer 4 days of treatment for the prolonged treatment. Animal studies. 8–12 week old athymic nude mice were obtained from Taconic Farms (Hudson, NY). All experimental protocols were approved by Te University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee
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