Receptor Tyrosine Kinase Coactivation Networks in Cancer

Features of RTK coactivation networks. A, RTK-mediated signaling 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), whereas 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 modeling approaches simplify complex signaling networks and identify fragile points that have disproportionately large effects on signaling 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; ref. 16) or other intracellular network elements.