Therapeutic strategies to overcome ALK resistance in lung cancer

ALK tyrosine kinase inhibitors are current standard treatments for patients with ALK-rearranged non-small cell lung cancer. The development of crizotinib and a newer generation of ALK TKIs like ceritinib, alectinib, brigatinib and lorlatinib have conveyed prolonged survival outcomes in patients with ALK-driven cancers. Unfortunately, tumor cells invariably acquire resistance to these drugs through a diverse spectrum of biological mechanisms. On- and off-target resistance mechanisms emerge during the evolution of the patients disease, including ALK kinase domain mutations or ALK amplification and by-pass track activation of oncogenic signaling pathways. In this chapter, we will discuss the current preclinical and clinical evidences supporting different treatment strategies aiming to prevent or overcome the biological processes that drive ALK TKI resistance.