Table 1.

ErbB2 mutations associated with lapatinib resistance and survival IC50 analysis of cloned ErbB2 resistance-associated mutations expressed in Ba/F3 cells

ErbB2 mutationClonesMutation frequency (%)Protein domainBa/F3 cell lineLapatinib
EXEL-7647
IC50 (nmol/L)SDIC50 (nmol/L)SD
NoneNANANAV659E962114825
C630Y11.1EC
E717K11.1JMV659E_E717K46150294103
E719K11.1JM
E719G11.1JMV659E_E719G894162436
L726F89.0KinaseV659E_L726F1,0566531588
T733I22.2KinaseV659E_T733I67025515153
L755S55.6KinaseV659E_L755S2,86174637113
P780L44.5KinaseV659E_P780L1,12776448129
S783P55.6KinaseV659E_S783P3,273518161
L785F1516.9KinaseV659E_L785F1,15465554175
T798I3539.3KinaseV659E_T798I3,339289419131
Y803N11.1KinaseV659E_Y803N49617012324
E812K66.7KinaseV659E_E812K407741871
D821N11.1KinaseV659E_D821N249531849
V839G11.1KinaseV659E_V839G28614968
L915M11.1KinaseV659E_L915M2535315289
S1002R11.1CT
  • NOTE: Mutations identified by DNA sequencing in lapatinib-resistant cells were introduced into ErbB2 V659E expression constructs by site-directed mutagenesis to resynthesize the resistance-associated mutations. The mutant ErbB2 constructs were expressed in Ba/F3 cells, and stable expressing cells were selected. Cell viability was measured following 48-h compound treatment in the absence of IL-3. Viability IC50 values were calculated from a 10-point lapatinib or EXEL-7647 dose response.

    Abbreviations: EC, extracellular; JM, juxtamembrane; CT, COOH terminus.