Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer

Abstract

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and many kinds of ALK fusion genes have been found in a variety of carcinomas. There is almost no detectable expression of ALK in adults. However, through ALK gene rearrangement, the resultant ALK fusion protein is aberrantly overexpressed and dimerized through the oligomerization domains, such as the coiled-coil domain, in the fusion partner that induces abnormal constitutive activation of ALK tyrosine kinase. This results in dysregulated cell proliferation. ALK gene rearrangement has been observed in 3%-5% of non-small-cell lung cancers, and multiple ALK inhibitors have been developed for the treatment of ALK-positive lung cancer. Among those inhibitors, in Japan, 3 (4 in the USA) ALK tyrosine kinase inhibitors (TKIs) have been approved and are currently used in clinics. All of the currently approved ALK-TKIs have been shown to induce marked tumor regression in ALK-rearranged non-small-cell lung cancer; however, tumors inevitably relapse because of acquired resistance within a few years. This review focuses on ALK-TKIs, their resistance mechanisms, and the potential therapeutic strategies to overcome resistance.

Keywords: ALK; fusion gene; mutation; resistance; tyrosine kinase inhibitor.

Figure 1

Half maximal inhibitory concentration values of the indicated Ba/F3 cells (EML4‐ALK WT or major resistant mutants) are shown in dot plots. A, IC ₅₀ data were obtained from Gainor et al49 B, The L1198F double mutant confers resistance to lorlatinib but is extremely sensitive to crizotinib. IC ₅₀ data were obtained from Shaw et al62

Figure 2

Structure of anaplastic lymphoma kinase (ALK) (WT or crizotinib resensitized mutant C1156Y + L1198F) is depicted using the indicated crystal structure analysis data (Protein Data Bank: 2XP2 [left] and 5AAB [right])

Figure 3

Bypass pathway activation‐mediated anaplastic lymphoma kinase‐tyrosine kinase inhibitor (ALK‐TKI) resistance (stromal cell‐mediated ligand secretion from tumor‐ or stromal cell‐mediated receptor tyrosine kinase activation). Left panel, cKIT gene amplification with stem cell factor (SCF) (a ligand of cKIT) secretion from stromal cell‐mediated crizotinib resistance. Middle panel, hepatocyte growth factor (HGF) upregulation led to cMET activation‐mediated resistance. HGF was secreted from tumor or stromal cells. Otherwise, cMET gene amplification solely induced the activation of cMET, which resulted in ALK‐TKI resistance. Right panel, ERBB receptor, including epidermal growth factor receptor (EGFR) activation‐mediated resistance. Various ligands for the ERBB family can induce activation of ERBB receptors and induce resistance. CAF, cancer‐associated fibroblast; EML4, echinoderm microtubule‐associated protein‐like 4; NRG, neuregulin; TGF‐A, transforming growth factor‐α