Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation.
Activating mutations in the epidermal growth factor receptor (EGFR) characterize a subset of non-small cell lung cancers (NSCLC) with extraordinary sensitivity to targeted tyrosine kinase inhibitors (TKI). A single secondary EGFR mutation, T790M, arising in cis with the primary activating mutation, confers acquired resistance to these drugs. However, the T790M mutation is also detected in the absence of drug selection, suggesting that it may provide a growth advantage. We show here that although T790M alone has only a modest effect on EGFR function, when combined with the characteristic activating mutations L858R or del746-750, it results in a dramatic enhancement of EGFR activity. The double mutants show potent ligand-independent receptor autophosphorylation associated with altered cellular phenotypes, soft agar colony formation, and tumorigenesis in nude mice. The significant gain-of-function properties of these double mutants may explain their initial presence before drug selection and their rapid selection as the single drug resistance mutation during therapy with gefitinib/erlotinib, and suggests that they may contribute to the adverse clinical course of TKI-resistant NSCLC.
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nadia
N
Godin-Heymann
Ianthe
I
Bryant
Miguel N
MN
Rivera
Lindsey
L
Ulkus
Daphne W
DW
Bell
David J
DJ
Riese
Jeffrey
J
Settleman
Daniel A
DA
Haber
D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic; D003114:Colony-Forming Units Assay; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010641:Phenotype; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics
D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors