Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy: RAS acts as contextual signaling hub

Abstract

Cancer initiation and development are increasingly perceived as systems-level phenomena, where intra- and inter-cellular signaling networks of the ecosystem of cancer and stromal cells offer efficient methodologies for outcome prediction and intervention design. Within this framework, RAS emerges as a 'contextual signaling hub', i.e. the final result of RAS activation or inhibition is determined by the signaling network context. Current therapies often 'train' cancer cells shifting them to a novel attractor, which has increased metastatic potential and drug resistance. The few therapy-surviving cancer cells are surrounded by massive cell death triggering a primordial adaptive and reparative general wound healing response. Overall, dynamic analysis of patient- and disease-stage specific intracellular and intercellular signaling networks may open new areas of anticancer therapy using multitarget drugs, drugs combinations, edgetic drugs, as well as help design 'gentler', differentiation and maintenance therapies.

Keywords: Cancer attractors; Cancer stem cells; Combination therapies; N=1 trials; RAS; Signaling networks.