title: Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells.
abstract: Pancreatic cancer is currently the fourth most common cancer, is increasing in incidence and soon will be the second leading cause of cancer death in the USA. This is a deadly malignancy with an incidence that approximates the mortality with 44,000 new cases and 36,000 deaths each year. Surgery, although only modestly successful, is the only curative option. However, due the locally aggressive nature and early metastasis, surgery can be performed on less than 20% of patients. Cytotoxic chemotherapy is palliative, has significant toxicity and improves survival very little. Thus new treatment paradigms are needed desperately. Due to the extremely high frequency of KRAS gene mutations (>90%) detected in pancreatic cancer patients, the roles of the epidermal growth factor receptor (EGFR), Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTORC1/GSK-3 pathways have been investigated in pancreatic cancer for many years. Constitutively active Ras can activate both of these pathways and there is cross talk between Ras and EGFR which is believed to be important in driving metastasis. Mutant KRAS may also drive the expression of GSK-3 through Raf/MEK/ERK-mediated effects on GSK-3 transcription. GSK-3 can then regulate the expression of NF-kappaB which is important in modulating pancreatic cancer chemoresistance. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about these pathways and how their deregulation can lead to cancer. Multiple inhibitors to EGFR, PI3K, mTOR, GSK-3, Raf, MEK and hedgehog (HH) have been developed and are being evaluated in various cancers. Current research often focuses on the role of these pathways in cancer stem cells (CSC), with the goal to identify sites where therapeutic resistance may develop. Relatively novel fields of investigation such as microRNAs and drugs used for other diseases e.g., diabetes, (metformin) and malaria (chloroquine) have provided new information about therapeutic resistance and CSCs. This review will focus on recent advances in the field and how they affect pancreatic cancer research and treatment.
authors.affiliation: Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Fitzgerald
authors.affiliation: Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: Kvin
authors.initials: K
authors.lastname: Lertpiriyapong
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology & Functional Genomics, Section of Pathology & Oncology, Via Androne, Catania, Italy, University of Catania, Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology & Functional Genomics, Section of Pathology & Oncology, Via Androne, Catania, Italy, University of Catania, Catania, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Candido
authors.affiliation: Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy.
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Steelman
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. Electronic address: mccubreyj@ecu.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D038362:Glycogen Synthase Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cancer stem cells; Drug resistance; EGFR; GSK-3; KRas; Metformin; miRs