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Background - Drugs designed to bind specific targets fostered dramatic improvements in the treatment of human tumors. However virtually all patients develop resistance to targeted therapies. Most of the chemotherapeutic agents inhibit kinases that transduce signals using survival pathways, such as PI3K-AKT and MAPK pathways, that have common downstream effectors. As a consequence, drug resistance can be the result of survival pathway re-activation via genetic or non-genetic mechanisms.
Hypothesis - Among the mechanisms that induce drug resistance via survival pathways reactivation, increased levels of receptor tyrosine kinase ligands can rescue oncogene signaling, which is inhibited by drugs. The sources for ligands production can be autocrine, paracrine or systemic. Several experimental evidences show that autocrine signaling is implicated in mechanisms of resistance to several kinase inhibitors.
Experimental Design - We shall analyze a comprehensive dataset of pharmacological data, in combination with genomic, and transcriptomic data, to build networks of cell-binding, that will be used for analyzing the sensing properties of the tumor cell lines, and networks of cell-production, that will be used for characterizing the secreting properties of the tumor cell lines.