Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers
Ces deux études proposent des hypothèses pour expliquer pourquoi les inhibiteurs d'EGFR, comme l'erlotinib, sont beaucoup plus efficaces sur des tumeurs pulmonaires que sur des glioblastomes présentant des mutations activant l'expression d'EGFR
While mutational activation of the Epidermal Growth Factor Receptor (EGFR) features prominently in glioma and non-small-cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles, quantifying kinase site occupancy by clinical inhibitors using novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase site occupancy in glioma-derived EGFRvIII, compared to NSCLC-derived EGFR mutants. Kinase site occupancy correlated directly with cell cycle arrest. EGFRvIII released erlotinib rapidly compared to wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly. These data suggest kinase site occupancy as a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response.
Cancer Discovery , résumé, 2012