The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells

Abstract

The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing. In this review, we discuss the signalling behaviour of RAS and RAF proteins in normal and in cancer cells, and the emerging systems-level properties of the RAS-to-ERK signalling network. We argue that to understand the dynamic complexities of this control system, mathematical models including mechanistic detail are required. Looking into the future, these dynamic models will build the foundation upon which more effective, rational approaches to cancer therapy will be developed.

Clinical responses to ERK inhibition in BRAF V600E-mutant colorectal cancer predicted using a computational model

“…52 Yet despite the wealth of pre-clinical data posing MAPK as a critical oncogenic pathway, clinical activity has been minimal outside of melanoma. 53 In addition to the well-established robustness of the MAPK network due to feedback circuits and pathway cross-talk, 54 our results provide two critical explanations for this. First, the hypersensitive pMEK:pERK relationship necessitates near-complete target suppression for antitumor activity, and this may be difficult to achieve with tolerable doses of MEK inhibitor monotherapies.…”

Two is better than one; toward a rational design of combinatorial therapy

“…In many cases, negative feedbacks allow the system to reset itself back to the pre-stimulated state after the stimuli, a dynamic property also known as adaptation [25,26]. While adaptation in signaling pathways broadens the range of signal sensing and allows sensitive response to input change, it can also blunt drug response and cause drug resistance.…”

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

“…Our short summary and the papers of this special issue [25,29,30,33,36,39,42,52,57] highlight the promises and challenges of using signaling networks (including RAS-related signaling events) in the description of cancer initiation and development, metastasis and the emergence of drug resistance. As key messages we emphasize that…”

“…The approaches outlined above and in the contributions of this special issue [25,29,30,33,36,39,42,52,57] may overcome the current Nietzschean dilemma of cancer cell targeting: “what does not kill me makes me stronger” [60]. …”

“…As the starting contribution of the three papers of this issue describing the complexity of the RAS-centered signaling network, Boris Kholodenko and co-workers [36] delineate the intricate dynamic control and plasticity of RAS-to-ERK signaling including feedback-activation, noise-rejection, ultrasensitivity, integral feedback, negative feedback amplification and perfect adaptation both at the single cell level and in a cell population context. They convincingly argue that this complexity can be tackled only by using mathematical models of network dynamics leading to the development of dynamically fine-tuned, rational cancer therapy design [37,38].…”