Fig. 6: Collateral sensitivities of evolutionary intermediates. | Nature Communications

Fig. 6: Collateral sensitivities of evolutionary intermediates.

From: Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures

Fig. 6

a Impact of pre-exposure to 0.5 µM alectinib for the indicated periods on sensitivity to alectinib and lapatinib, measured by Cell Titer Glo assay. One-way ANOVA was used for both drugs (p < 0.0001). Adjacent time points were compared using Sidak’s multiple comparison tests (***p < 0.001 and ****p < 0.0001). Mean ± SD of experimental replicates are shown. n = 3, representing separate wells, for naive control and erAlec H3122 cells. n = 6 wells (3 wells each of 2 biological replicates) for cells pre-exposed to alectinib. Data for one of the biological replicates is missing in week 6. b Illustration of association of evolving resistance to alectinib with collateral sensitivity to lapatinib. c Lapatinib can prevent the development of resistance to alectinib in vitro, both as a combination treatment, or in drug cycling. Green shading indicates switching from alectinib to lapatinib monotherapy. Residual signal in the combination therapy and cycling groups reflects autofluorescence, as visual examination revealed lack of surviving tumor cells. Mean ± SD of experimental replicates (n = 3 representing separate wells for DMSO and lapatinib monotherapy, n = 6 for the remaining groups) are shown. d Change in volume of H3122 xenograft tumors treated with indicated therapies; treatment was initiated 3 weeks post tumor implantation. Green shading indicates switching from alectinib to lapatinib monotherapy or vehicle control. Mean values ± SE are shown; n = 6 for lapatinib monotherapy, n = 10 for alectinib monotherapy, switching between alectinib and lapatinib, and alectinib/lapatinib combination, n = 9 for vehicle control, replicates represent separate tumors. e Evolving resistance interpreted through a fitness landscape metaphor. Naive cells occupy a local fitness peak. Drug exposure reshapes the landscape, turning this fitness peak into a fitness trough. Different ALK inhibitors act on partially distinct outliers, directing their evolution toward distinct fitness peaks.

Back to article page