Receptor tyrosine kinase coactivation networks in cancer

Abstract

Cancer cells employ multiple mechanisms to evade tightly regulated cellular processes such as proliferation, apoptosis, and senescence. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase (RTK) coactivation as an important mechanism by which cancer cells achieve chemoresistance. This mini-review discusses our current understanding of the complex and dynamic process of RTK coactivation. We highlight how systems biology and computational modeling have been employed to predict integrated signaling outcomes and cancer phenotypes downstream of RTK coactivation. We conclude by providing an outlook on the feasibility of targeting RTK networks to overcome chemoresistance in cancer.

Figure 1. Features of RTK coactivation networks

(A) RTK-mediated signalling pathways share multiple elements and inhibiting the dominant RTK often results in the compensatory recruitment of downstream components by secondary RTKs. Examples of dominant RTKs include EGFR (2, 4, 10) and ErbB2 (15), while secondary RTKs such as c-Met, PDGFR and IGF-1R (4, 9, 15) have been reported. These RTK coactivation events converge on a number of fragile points in the network such as AKT (6). (B) Kinetic modelling approaches simplify complex signalling networks and identify fragile points that have disproportionate large effects on signalling and phenotypic output. (C) Effective treatment strategies (green) include targeting of multiple RTKs or fragile points determined by the implementation of network models. Alternative resistance mechanisms may arise in response to these therapeutic interventions (red) which may include activation of alternative RTKs (e.g. Axl (16)) or other intracellular network elements.