title: Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway.
abstract: Mitogen-activated protein kinases (MAPK) are involved in a complex network which regulates a variety of cellular processes including proliferation, survival and death. The molecular characterization of the pathway has shown aberrant activation in several human tumors, due to the deregulation of receptor tyrosine kinases or to mutations of pathway components. Progress in understanding the MAPK network has led to the development of target-specific agents in clinical trials. The relevance of MAPK in response and resistance to antitumor agents has been recognized, although the outcome of MAPK activation can vary depending on the molecular background of tumor cells and on the type of activated kinase. The canonical cascade of MAPK, i.e., depending on the Extracellular Signal-Regulated Kinases (ERK), can act in protective signalling pathways, thereby limiting DNA damage. Since tumor cell survival can be sustained by ERK and cross talk of ERK with other pathways, modulation of sensitivity to antitumor agents by targeting the ERK cascade appears to be an amenable approach. Indeed, ERK play a role in resistance to both cytotoxic and target-specific agents. Preclinical studies support the relevance of drug combination approaches to enhance the efficacy of antitumor treatments. Combinations of pharmacological inhibitors of the ERK cascade and conventional or target-specific antitumor agents may be helpful in an attempt to overcome drug resistance. A deeper understanding of the genetic alterations of tumor cells and of tumor heterogeneity as well as of drug resistance mechanisms is expected to contribute to the rational design of MAPK-mediated drug combinations that will lead to reversal of drug resistance.
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCSS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cossa
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival; D004249:DNA Damage; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases