Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer

Abstract

In the setting of recent exciting clinical results and numerous ongoing trials, Gainor and colleagues explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors in ALK-rearranged non-small cell lung cancer and found that an increased frequency and distinct spectrums of resistance mutations emerged with the more potent second-generation inhibitors. Their findings have important and immediate clinical implications as the resistance mutations detected impart differential sensitivities to available ALK inhibitors, thereby highlighting the need for sequential biopsies with molecular testing to determine the most effective treatment strategy upon disease progression. Cancer Discov; 6(10); 1084-6. ©2016 AACRSee related article by Gainor et al., p. 1118.

Figure 1. Summary of ALK kinase domain mutations found in samples with acquired resistance to first- and second-generation ALK tyrosine kinase inhibitors (TKIs)

Crizotinib is a first-generation ALK TKI. Ceritinib, Alectinib, and Brigatinib are second-generation ALK TKIs. Only those ALK TKIs evaluated in the manuscript by Gainor and colleagues were included in this figure.