title: Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling.
abstract: Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Massi
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Taverna
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Huifang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Gongda
authors.initials: G
authors.lastname: Xue
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000178:diet therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases