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Targeting EGFR/ERK/FOS Signaling As a Novel Approach for HPV-Positive Head and Neck Cancer Treatment

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Targeting EGFR/ERK/FOS Signaling As a Novel Approach for HPV-Positive Head and Neck Cancer Treatment PhD degree in Systems Medicine (curriculum in Molecular Oncology) European School of Molecular Medicine (SEMM), University of Milan and University of Naples “Federico II” Settore disciplinare: Bio/11 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck cancer treatment Alessandro Medda European Institute of Oncology (IEO), Milan Tutor: Prof. Susanna Chiocca European Institute of Oncology (IEO), Milan PhD Coordinator: Prof. Giuseppe Viale Anno accademico 2019-2020 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck Cancer Table of contents 1 Abstract ............................................................................................................. 9 2 Introduction ..................................................................................................... 10 2.1 Human Papillomaviruses ................................................................................... 10 2.1.1 Classification ......................................................................................................... 10 2.1.2 Structure and organization .................................................................................... 12 2.1.2.1 Viral Proteins ..................................................................................................... 12 2.1.3 HPV life cycle and infection ................................................................................... 16 2.1.3.1 Viral Attachment and Entry ................................................................................ 16 2.1.3.2 Genome Replication and Gene Expression ......................................................... 17 2.1.3.3 Assembly, Maturation and Viral Release ............................................................ 18 2.1.4 Non-Productive HPV Infection and Transformation ............................................... 19 2.2 Head and Neck Cancer ....................................................................................... 20 2.2.1 Background and epidemiology of Head and Neck cancer ....................................... 20 2.2.2 Anatomy and risk factors of Head and Neck cancer ............................................... 21 2.2.3 The role of HPV in Head and Neck cancers............................................................. 22 2.2.4 Primary and secondary prevention for Head and Neck cancer ............................... 23 2.2.5 Treatment strategies for Head and Neck cancer .................................................... 26 2.3 The molecular landscape of Head and Neck cancer ........................................... 27 2.3.1 Molecular features of HPV- HNSCC ........................................................................ 28 2.3.2 Molecular features of HPV-induced carcinogenesis. .............................................. 30 2.3.2.1 The EGFR pathway ............................................................................................. 30 2.3.2.2 The PI3K/Akt/mTOR axis .................................................................................... 32 2.3.2.3 The role of MAPKs ............................................................................................. 33 2.4 Aims of the study ............................................................................................... 36 3 Material and Methods ..................................................................................... 37 3.1 Cells ................................................................................................................... 37 3.2 Transductions and Transfections ....................................................................... 38 3.3 Plasmids ............................................................................................................ 39 3.4 RNA Extraction, Reverse Transcription and qRT-PCR ......................................... 40 3.5 Immunoblotting and Antibodies ........................................................................ 41 3.6 Growth curves ................................................................................................... 42 3.7 Half Maximal Inhibitory Concentration Analysis ............................................... 43 3.8 Apoptosis assay and flow cytometry ................................................................. 43 1 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck Cancer 3.9 Drugs and Treatments ........................................................................................44 3.10 Statistical analysis ..............................................................................................44 4 Results ............................................................................................................. 45 4.1 Downregulation of HPV16 E6/E7 reduces cell proliferation in some, but not all HPV+ HNSCC cell lines .............................................................................................................45 4.2 Kinase inhibitors decrease HPV16 E6/E7 expression in HNSCC cell lines ............54 4.3 Sorafenib induces downregulation of E7 in all HPV+ HNSCC cell lines ................55 4.4 Sorafenib downregulates E6/E7 also in the presence of autophagic and proteasomal inhibition............................................................................................................56 4.5 Sorafenib downregulates E6/E7 mRNA levels ....................................................57 4.6 Sorafenib induces apoptosis in some HPV+ and HPV- HNSCC cell lines ..............59 4.7 Sorafenib sensitivity varies among HNSCC cell lines but not between HPV+ and HPV- cells 61 4.8 EGFR/MEK/ERK/JNK pathways regulate E7 expression ......................................62 4.9 Effects of Ravoxertinib and Tanzisertib on E6/E7 expression upon EGF stimulation 63 4.10 Gain and loss of function of c-fos affect HPV16 E6/E7 expression ......................66 4.11 HPV16 E6/E7 mRNA expression correlates with JUN and FOS ............................68 4.12 HPV+ HNSCC cell lines are more sensitive to Ravoxertinib than HPV- HNSCC cell lines 70 5 Discussion ........................................................................................................ 72 5.1 Conclusions and outlook ....................................................................................77 6 Appendix A - HPV and autophagy in Head and Neck Cancer ........................... 79 6.1 Introduction .......................................................................................................79 6.2 Material and methods ........................................................................................80 6.2.1 Cells...................................................................................................................... 80 6.2.2 Transductions, transfections, and plasmids ........................................................... 81 6.2.3 Library preparation, RNA sequencing and GSEA .................................................... 81 6.2.4 Electron microscopy ............................................................................................. 81 6.2.5 Ethics Statement................................................................................................... 82 6.3 Results................................................................................................................82 6.3.1 Autophagic compartments are deregulated by HPV16 in Head and Neck Cancer cells 82 6.3.2 HPV16 E6/E7 oncoproteins downregulate autophagy genes expression ................ 84 2 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck Cancer 6.3.3 TP53INP1 is regulated by E6/E7 expression ........................................................... 85 6.4 Discussion .......................................................................................................... 86 7 Bibliography .................................................................................................... 87 8 AcknowledgeMents ....................................................................................... 114 3 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck Cancer List of abbreviations in alphabetical order AGW Anogenital warts AML Acute myeloid leukemia AP-1 Activating protein-1 ATF Activating transcription factors ATF/CREB Activating transcription factor, cyclic AMP-responsive element- binding ATG Autophagy related gene ATM ataxia-telangiectasia mutated ATR ataxia-telangiectasia and Rad3-related protein BPE Bovine pituitary extract CDK Cyclin-dependent kinase CDKN2A Cyclin dependent kinase inhibitor 2A ChIP Chromatine immunoprecipitation CNA Copy number alteration CRISPR/Cas9 Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 DDR DNA damage response DEG Differential gene expression Dlg1 Drosophila disc large tumor suppressor 1 DMEM Dulbecco's Modified Eagle Medium E2F E2 transcription factor E6AP E6-associated protein ECL Enhanced chemiluminescent EDTA Ethylenediaminetetraacetic acid EFG Epidermal growth factor EFGR Epidermal growth factor receptor eIF4E Eukaryotic transcription factor 4E Elk1 ETS Like-1 protein EMT Epithelial-mesenchymal transition ERK Extracellular signal-regulated kinase FBS Fetal bovine serum GAPDH Glyceraldehyde-3-Phosphate Dehydrogenase GPCR G protein-coupled receptor 4 Targeting EGFR/ERK/FOS signaling as a novel approach for HPV-positive Head and Neck Cancer gRNA Guide RNA GSEA Gene Set
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