Institute of Information Science, Academia Sinica

Tumorgenesis is an evolutionary process that gives rise to high degree of heterogeneity among cancer cells. This heterogeneity usually limits the efficacy of a single anticancer drug to fully eliminate all cells in a tumor. One approach for overcoming therapy resistance is by combining multiple drugs. Nevertheless, the current drug combination designs remain mostly relying on the trial and error approach. Here, we use dynamics of signaling molecules in single cells to help guide the design of drug combinations. Specifically, we showed that inhibition of the oncogene MDMX led to temporal changes in cellular state through biphasic dynamics of p53: an initial post-mitotic pulse followed by low-amplitude oscillations. When combined with DNA damage, the effects of MDMX was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase depletion of MDMX inhibited cell death. Therefore a quantitative understanding of signal dynamics and cellular state after drug treatment can be important for designing an optimal schedule of drug combinations.