title: Signaling pathways modulating dependence of lung cancer on mutant epidermal growth factor receptor and mechanisms of intrinsic and acquired resistance to tyrosine kinase inhibitors.
abstract: A new era in lung cancer targeted therapy arrived with the discovery of a subset of lung adenocarcinomas harboring activating mutations of the epidermal growth factor receptor (EGFR), whose tyrosine kinase activity can be selectively blocked by small molecule pharmaceuticals referred as tyrosine kinase inhibitors (TKIs). This was the starting point for a less toxic and more effective treatment strategy for a disease that has historically presented as chemorefractory and highly lethal. In spite of this progress, only 80% of the patients treated with this class of compounds will obtain a clinical benefit, of variable magnitude and duration, with remaining patients being primarily refractory to the treatment. Moreover, responding tumors will eventually develop acquired resistance to TKIs and progress to more advanced stages. In this review we summarize the current knowledge with regard to the mechanisms leading to tumor regression and the modifiers of this primary response that determine significant variability in sensitivity of tumors harboring EGFR activating mutations, ranging from complete remission to primary refractoriness. We also analyze the mechanisms of secondary resistance and the strategies the scientific community is exploring in order to overcome these barriers.
authors.forename: Luciano
authors.initials: L
authors.lastname: Wannesson
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.forename: Carlota
authors.initials: C
authors.lastname: Costa
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Molina-Vila
authors.affiliation: Oncology Institute of Southern Switzerland, CH6500 Bellinzona, Switzerland. Luciano.Wannesson@eoc.ch.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors