CI 1033 more potently inhibited more potently and EGFR phosphorylation induced cell death than HKI 272. Both inhibitors induced cell death at submicromolar Cabozantinib structure concentrations in HCC827 cells, consistent with the reported hyper-sensitivity of the EGFR746 750 mutant to ATP site aggressive EGFR kinase inhibitors in vitro and in lung cancer patients. In conclusion, these results show that EGFR mutant GBM cell lines need EGFR kinase activity for survival and point toward differences in EGFR kinase inhibitor responsiveness between EGFR kinase domain mutants and EGFR ectodomain mutants. 2. Enhanced sensitivity of EGFR ectodomain mutants to lapatinib Crystal structures of the EGFR catalytic domain in complex with ATP site aggressive EGFR kinase inhibitors have identified different receptor conformations. In complex together with the FDA approved drug lapatinib/GW572016, the EGFR kinase domain is within an inactive conformation. In complex with erlotinib/OSI 74, the EGFR kinase domain assumes an energetic conformation. Because HKI 272 binds the inactive conformation of the EGFR kinase domain and the active conformation is likely bound by CI 1033, we hypothesized Extispicy that conformationspecific binding to EGFR may possibly describe the differential response of GBM cell lines with EGFR EC mutants to those two compounds. If correct, lapatinib should also show superior activity against EGFR EC mutants than erlotinib. To examine this problem, we first stated several EGFR ectodomain mutants in NR6 fibroblasts which do not detectably convey EGFR or other ErbB family members and are popular for the biochemical characterization of EGFR family members. After drawing steady sublines for every single EGFR allele, we examined changes in phosphorylation in response to equimolar concentrations of erlotinib or lapatinib. While both inhibitors reduced EGFR phosphorylation in a dose-dependent manner, lapatinib showed dramatically greater effectiveness supplier Ibrutinib against all analyzed EGFR ectodomain mutants and, less significantly, also against wild-type EGFR. We obtained comparable results in human astrocytes which do convey endogenous wildtype EGFR and which we further engineered to overexpress either wildtype EGFR or the 2 most frequent EGFR ectodomain mutants in GBM. We next extended our comparison between erlotinib and lapatinib to GBM cell lines endogenously showing EGFR ectodomain mutants. These included SKMG3 and SF268 cells as well as a third point recently reported to harbor the G598V EGFR ectodomain mutant. To standard our results against previous focus on EGFR kinase domain mutants, our experiments also involved the lung cancer cell lines HCC827, HCC4006, and H3255. Much like our leads to NR6 cells and astrocytes, lapatinib was stronger than erlotinib at curbing basal phosphorylation of most examined EGFR ectodomain mutants.