Compensatory pathways in oncogenic kinase signaling and resistance to targeted therapies: six degrees of separation.
The efficacy of targeted therapies against mutationally activated kinases is typically limited by the engagement of growth-promoting cues that compensate for inhibition of the targeted kinase. Initial studies have highlighted the contribution of genomic alterations, functional characteristics, and signaling feedback loops--all intrinsic to cancer cells--in sustaining such substitute activities. New evidence now indicates that the relative expression of growth factor ligands produced by the tumor microenvironment can relay redundant survival pathways, which may broadly impair responsiveness to kinase inhibitors.
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment, and Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy. livio.trusolino@ircc.it
Livio
L
Trusolino
Andrea
A
Bertotti
D019008:Drug Resistance, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases