Mechanisms of Resistance to Target Therapies in Non-small Cell Lung Cancer.
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i.e. MET amplification, KRAS mutations); (3) phenotype transformation (to small cell lung cancer, epithelial-mesenchymal transition). These basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. Novel-generation molecules include osimertinib, for EGFR-T790M-positive patients, and new ALK-TKIs. Nevertheless, the possible concomitant presence of multiple resistance mechanisms, as well as their heterogeneity among cells and disease localizations, makes research in this field particularly arduous. In this chapter, available evidence and perspectives concerning precise mechanisms of escape to pharmacological inhibition in oncogene-addicted NSCLC are reported for single targets, including but not limited to EGFR and ALK.
Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, Parma, 43126, Italy.
Francesco
F
Facchinetti
Thoracic Oncology Unit, Department of Medical Oncology 1, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Claudia
C
Proto
Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, Parma, 43126, Italy.
Roberta
R
Minari
Thoracic Oncology Unit, Department of Medical Oncology 1, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Marina
M
Garassino
Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, Parma, 43126, Italy. mtiseo@ao.pr.it.
Marcello
M
Tiseo
D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
ALK; EGFR; NSCLC; ROS-1; Resistance mechanisms; T790M