Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks

Abstract

SUMMARY Crosstalk and complexity within signaling pathways, and their perturbation by oncogenes, limits component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be re-wired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous co-administration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis—using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling— revealed an approach for altering the intrinsic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.

Navigating cancer network attractors for tumor-specific therapy

“…and Pawson 66 several years ago, new pharmaceutical strategies that target networks instead of single proteins are becoming available 47,48 . We predict this trend will not only continue, but also include recent advances that highlight the possibility to 'cure' networks using time-and order-dependent therapies 68 . In coming years, the discovery of resistant, metastatic, tissue or cell-specific networks could lead to an even greater advance in the field of network medicine (Fig.…”

“…Recent work by the Yaffe laboratory represents a clear leap forward within the field of network medicine 68,69 . Following network modeling, Yaffe and colleagues 68 managed to decode the signaling network dynamics that drive resistance to DNA-damaging chemotherapy.…”

“…2d). Ideally, network drugs, such as the aforementioned order-and time-dependent combination 68 , should then be chosen based on the interpretation of sequencing as well as the proteomic and phenotypic analysis of tumor cells and tested on the tumor-specific cell lines and xenograft model. The best-performing combination should ultimately be transferred back to the patient (Fig.…”

A 1024-sample serum analyzer chip for cancer diagnostics

“…Our approach is thus high-throughput, precise, sensitive, cost-effective, and widely applicable, and thus should find many uses in diagnostics, as well as systems biology, 44 specifically in signal pathway analysis, where it is becoming increasingly necessary to quantitate many proteins in large numbers of samples. 45 …”

Logic Modeling in Quantitative Systems Pharmacology

“…Docetaxel is known to target β‐tubulin, which is related to the cytoskeleton and has no clear effect on our network of interest. However, it is known that cytotoxic treatments can also rewire cell signaling networks 71. More measurements in the docetaxel condition could allow studying cell signaling rewiring with logic models through network optimization.…”