Mechanisms of Drug Resistance in Cancer Therapy

Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo, Facchinetti, Francesco, Proto, Claudia, Minari, Roberta, Garassino, Marina, Tiseo, Marcello

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.