Modeling Signaling Networks to Advance New Cancer Therapies

Abstract

Cell signaling pathways control cells' responses to their environment through an intricate network of proteins and small molecules partitioned by intracellular structures, such as the cytoskeleton and nucleus. Our understanding of these pathways has been revised recently with the advent of more advanced experimental techniques; no longer are signaling pathways viewed as linear cascades of information flowing from membrane-bound receptors to the nucleus. Instead, such pathways must be understood in the context of networks, and studying such networks requires an integration of computational and experimental approaches. This understanding is becoming more important in designing novel therapies for diseases such as cancer. Using the MAPK (mitogen-activated protein kinase) and PI3K (class I phosphoinositide-3' kinase) pathways as case studies of cellular signaling, we give an overview of these pathways and their functions. We then describe, using a number of case studies, how computational modeling has aided in understanding these pathways' deregulation in cancer, and how such understanding can be used to optimally tailor current therapies or help design new therapies against cancer.

Patient‐specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies

“…Charting the dynamic wiring of signaling networks is of paramount importance to understand how cells respond to their environment. Identifying the differences in this wiring between normal and cancerous cells can shed light on the pathophysiology of tumors and pave the way for novel therapies (Werner et al , ; Saez‐Rodriguez et al , ; Zañudo et al , ). A powerful tool to gain insight into these processes is to monitor the response of cells to multiple perturbations.…”

Logic Modeling in Quantitative Systems Pharmacology

“…18 Several modeling formalisms exist to deal with complex gene regulatory and signaling network structures. 11,21,22 Because models can also provide insights into a drug's mode of action, scientists are also working towards building bridges between drug design and network modeling techniques. 9,23,24 Among the modeling techniques, logic(al) modeling has proven to be very versatile and able to provide useful biological insights.…”

“…[8][9][10] It is known that many diseases involve alterations in the signaling pathways used by cells to interpret the cues from their environment. [11][12][13][14] Likewise, many drugs are designed to target components of these signaling pathways. These different pathways are not merely linear signaling conduits activated by different stimuli, but are also interconnected via crosstalk mechanisms to regulate each other, giving rise to signaling networks.…”

Looking beyond the cancer cell for effective drug combinations

“…Combinations of small-molecule inhibitors or biologics that target signaling receptors can be analyzed through mechanistic models of the downstream signaling networks as, for example, logic circuits, causal networks, or differential equations describing the underlying biochemical reactions [79–83]. However, if we want to consider a combination of a small-molecule inhibitor that targets a kinase and a drug that affects metabolism or gene regulation, we would need integrated models of both molecular layers.…”