The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer.
The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority ( approximately 80-90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.
Kono
Scott A
SA
Department of Medicine, University of Colorado at Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Marshall
Marianne E
ME
Ware
Kathryn E
KE
Heasley
Lynn E
LE
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D017468:Receptors, Fibroblast Growth Factor; D066246:ErbB Receptors