How Targeted Therapies Exploit Signaling (src) and Metabolic (Glucose) Overdependencies in Cancer Homeostasis

Unbiased inquiries into signaling and metabolism using phospho-proteomics have repeatedly pointed us to networks involving negative and positive feedback, cross-talk, synergy, and unexpected results.  Examples include negative feedback of Src signaling in kinase inhibitor-resistant Bcr-Abl-driven leukemias (Rubbi et al.); feed-forward, synergistic amplification of signaling upon metabolic stress leading to catastrophic death (Graham et al.); synergistic co-treatments that can prevent kinase inhibitor resistance; and the identification of druggable tyrosine signaling in prostate cancer, a tumor type in which tyrosine signaling mutations are rare (Drake et al.). In sum, these examples provide illustrations of how the signaling and metabolic states of cancer cells, while homeostatic, can be relatively unstable to disruptive perturbations.