Overview of rationale and clinical trials with signal transduction inhibitors in lung cancer.
Most cellular proto-oncogenes encode proteins that participate in signaling pathways by which cells receive and execute instructions that lead to mitogenesis, differentiation, lineage determination, cell migration, extracellular matrix production, and apoptosis, among others. These proto-oncogene protein products include transmembrane receptor tyrosine kinases and receptor substrates, serine/threonine kinases, receptor adaptor molecules, low-molecular-weight GTPases, and transcription factors that, when overexpressed or mutationally activated, can lead to cell transformation and tumor progression. The large number of oncogenic protein tyrosine kinases plus the rare presence of phosphotyrosine in nontransformed cells argue persuasively that tyrosine phosphorylation and activation of signaling molecules downstream from receptor tyrosine kinases are critical events in growth control and transformation and are, therefore, rational targets for anticancer molecular therapies. We will review some of the more recent treatment strategies in non-small cell and small cell lung cancer targeted to dysregulated signaling pathways that are causally associated with tumor maintenance and progression.
Arteaga
Carlos L
CL
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA.
Khuri
Fadlo
F
Krystal
Geoffrey
G
Sebti
Said
S
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002471:Cell Transformation, Neoplastic; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000187:drug effects; D051231:Farnesyltranstransferase; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D012107:Research Design; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases