Intermediate Stages in Tumor Evolution Can Be Therapeutically Targeted

Tumor cells may develop drug resistance through a dynamic clonal evolution. This evolution can create collateral sensitivities whereby the tumor cells become sensitive to drugs at the expense of sensitivity to other drugs. Previous studies have focused on determining the resistance mechanisms after relapse; however, the dynamic nature of clonal evolution may lead to temporary exploitable sensitivities during drug treatment. Zhao and colleagues explored this idea by identifying collateral sensitivities at intermediate stages of tumor evolution, termed “temporal collateral sensitivities.” A mathematical model of step-wise clonal evolution simulated intermediate stages of drug selection and predicted a treatment window, or temporary collateral sensitivity, during which the cells might become sensitive to a different drug. This was tested in murine Ph⁺ acute lymphoblastic leukemia cells, which are driven by the BCR–ABL1 fusion kinase, selected with the BCR–ABL1 inhibitor dasatinib to derive resistance. A pharmacologic screen discovered that resistant cells developed a collateral sensitivity to four other non-classic BCR–ABL1 kinase inhibitors. Mechanistically, the collateral sensitivity was determined to stem from preexisting BCR–ABL1 V299L mutations, which were selected for with dasatinib. However, as the V299L cells continued to evolve, compound mutations arose, which reduced the collateral sensitivity. Mathematical simulations suggested a therapeutic window of non-classic inhibitor sensitivity where BCR–ABL1 V299L cells predominated. The order in which the drugs were used affected the resistance mechanisms. For example, treatment with a non-classic inhibitor followed by dasatinib reduced the occurrence of V299L resistant subpopulations. Additional collateral sensitivities at intermediate-stage clonal evolution, as well as sensitivities at early- and late-stage evolution, were identified in a larger small-molecule screen. These findings were confirmed in mice, where non-classic inhibitors reduced dasatinib-resistant BCR–ABL1 V299L tumor burden. Together, these findings indicate that the development of tumor drug resistance is a dynamic process that creates temporal collateral drug sensitivities that may be exploitable for cancer therapy.

Zhao B, Sedlak JC, Srinivas R, Creixell P, Pritchard JR, Tidor B, et al. Exploiting temporal collateral sensitivity in tumor clonal evolution. Cell 2016 Feb 25 [Epub ahead of print].

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