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.