Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application.
The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC.
Division of Medical Oncology, 'S. G. Moscati' Hospital, Contrada Amoretta, Avellino, 83100, Italy.
Paolo
P
Maione
Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy.
Paola Claudia
PC
Sacco
Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
Assunta
A
Sgambato
Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
Francesca
F
Casaluce
Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy.
Antonio
A
Rossi
Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy.
Cesare
C
Gridelli
ALK rearrangements; AZD9291; CO-1686; EGFR mutations; T790M; alectinib; ceritinib; selective EGFR inhibitors