Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer

Abstract

Mutations in ALK are a common mechanism of acquired resistance to small molecule ALK inhibitors in ALK-rearranged lung cancer. Different mutants exhibit differential sensitivity to ALK inhibitors. Matching the mutational profile of the tumor with the appropriate ALK inhibitor is likely to be important to maximize benefit for patients.

Figure 1

Schematic representation showing the possible evolution of an ALK-rearranged lung cancer following sequential treatment with ALK inhibitors. This ALK inhibitor–naïve tumor is composed mainly of sensitive cells (blue) interspersed with rare cells harboring ALK point mutations (pink, orange, and green) or other ALK-independent alterations (blue hatched cells). During treatment with crizotinib, clones with mutations that confer resistance to crizotinib are positively selected. In this example, the more abundant clone harboring a G1269A mutation (orange) emerges, whereas clones harboring other resistance mutations, such as G1202R and I1171T, persist at low concentrations. Clones that have alterations other than ALK mutations that resist crizotinib will also persist (blue hatched cells). Upon treatment with ceritinib, cells with mutations that confer resistance to this drug (e.g., G1202R mutation, green cells) eventually dominate. Similarly, tumors with acquired resistance to alectinib are mostly composed of resistant clones that dominate after prolonged exposure to alectinib, for example, those with an I1171T ALK mutation or the G1202R mutation that also confers resistance to ceritinib. *For simplicity, these rare clones are depicted as present in the untreated tumor. This may be the case or, alternatively, they may also emerge during treatment. Further, the number and spectrum of clones present are likely to be unique for each tumor/patient.