Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments

TY - JOUR

T1 - Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments

AU - Koplev, Simon

AU - Longden, James

AU - Ferkinghoff-Borg, Jesper

AU - Blicher Bjerregård, Mathias

AU - Cox, Thomas R.

AU - Erler, Janine T.

AU - Pedersen, Jesper T.

AU - Voellmy, Franziska

AU - Sommer, Morten O.A.

AU - Linding, Rune

PY - 2017/9/19

Y1 - 2017/9/19

N2 - Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.

AB - Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations. Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.

KW - cancer

KW - chemotherapy

KW - sequential

KW - time-stagger

U2 - 10.1016/j.celrep.2017.08.095

DO - 10.1016/j.celrep.2017.08.095

M3 - Journal article

C2 - 28930675

AN - SCOPUS:85029583390

SN - 2211-1247

VL - 20

SP - 2784

EP - 2791

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -