RT Journal Article
SR Electronic
T1 Double <em>EGFR</em> mutants containing rare <em>EGFR</em> mutant types show reduced <em>in vitro</em> response to gefitinib compared with common activating missense mutations
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2142
OP 2151
DO 10.1158/1535-7163.MCT-08-1219
VO 8
IS 8
A1 Tam, Issan Yee-San
A1 Leung, Elaine Lai-Han
A1 Tin, Vicky Pui-Chi
A1 Chua, Daniel Tsin-Tien
A1 Sihoe, Alan Dart-Loon
A1 Cheng, Lik-Cheung
A1 Chung, Lap-Ping
A1 Wong, Maria Pik
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2142.abstract
AB Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in &gt;70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R+L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. [Mol Cancer Ther 2009;8(8):2142–51]