Feedback and redundancy in receptor tyrosine kinase signaling: relevance to cancer therapies

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2014-10, Vol.39 (10), p.465-474
• Main Authors: Sun, Chong, Bernards, René
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - adverse effects; Drug Resistance, Neoplasm - genetics; Drug Therapy, Combination - methods; Feedback; Humans; MAP Kinase Signaling System - drug effects; Molecular Targeted Therapy; Neoplasms - drug therapy; Oncogenes - drug effects; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; raf Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - physiology; Signal Transduction - physiology; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2014.08.010

•Feedback and redundancy in RTK signaling complicate cancer treatment.•Co-targeting primary oncogenic signaling and feedback can block drug resistance.•Treatment strategies need to take into account the complexity of signaling networks. Mammalian cells have multiple regulatory mechanisms to deal with perturbations in cellular homeostasis, including feedback loops and crosstalk between the major signaling pathways. While these mechanisms are critically required to help cells survive under dynamic physiological circumstances, they also pose an impediment to the effective treatment of cancer. In this review, we describe what has been learned about interactions between receptor tyrosine kinase-dependent signaling pathways, and how this knowledge can be used to design rational and more effective combination therapies for cancer.