Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine

Abstract

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)-ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC.

Figure 1

Genetic alterations of ALK. A, ALK point mutations identified in neuroblastoma. B, Schematic representations of ALK fusion proteins (top) and a list of various ALK fusion proteins described to date (bottom). Note that this list is not comprehensive.

Figure 2

Crizotinib resistant mutations mapped on ALK kinase domain. Reported crizotinib resistance mutations (point mutations and insertion mutation) in the ALK kinase domain were mapped on the structure data of ALK kinase domain (PDB: 2XP2) The bar graph on the right shows the frequency (reported cases) of each mutation detected directly from the crizotinib resistant patients.

Figure 3

Mechanisms of acquired resistance to ALK inhibitor therapy in ALK-rearranged NSCLC. Reported crizotinib, alectinib or ceritinib resistant mechanisms are shown. Bold characters indicate those resistance mechanisms which have been detected in patient tumor samples.