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Targeting mutant p53 in ALL
p53 re-sensitizes TP53mut ALL to the DNA-damaging agent doxorubicin, which is also used in treatment of pediatric ALL. TP53mut and TP53wt ALL cell lines and primograft samples were exposed to APR-246, doxoru- bicin, or to combinations of both at increasing concentra- tions. Strongly increased cell death rates were observed in all four TP53mut primografts and two cell lines upon com-
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bination treatment with APR-246, as compared to APR- 246 or doxorubicin alone, indicating synergistic activity for APR-246 and doxorubicin in TP53mut ALL (Figure 5A- F, Online Supplementary Table S3A). In TP53wt leukemias however, only doxorubicin showed cell death-inducing activity, which was not increased by adding APR-246 (Figure 5G-L, Online Supplementary Table S3B).
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Figure 5. APR-246 synergizes with doxorubicin. Synergistic activity of APR-246 in combination with the DNA-damage-inducing agent doxorubicin in TP53mut B-cell precursor (BCP)-acute lymphoblastic leukemia (ALL) cell lines (A, B) and TP53mut primograft leukemias (C-F) leading to doxorubicin re-sensitization, in contrast to no increased activity compared to treatment with doxorubicin alone in TP53wt cell lines (G, H) and TP53wt primograft ALL (I-L). Cell death (forward/side scatter cri- teria, flow cytometry) after exposure (primografts 24 h, cell lines 48 h) at indicated concentrations of APR-246 (APR), doxorubicin (DOX) or the combination (COMBI, 3 h APR-246 pre-incubation). Mean values ± standard deviation (SD) of three independent experiments, each performed in triplicate (cell lines: A, B, G, H). Mean values ± SD, three measurements (primografts: C-F, I-L). Combination indices (CI) indicating a strong synergistic (CI 0.1-0.3), a synergistic (CI <1), an additive (CI=1) or an antagonistic effect (CI>1) upon combination.
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