Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR- Activating Mutation

Abstract

The combination of gefitinib and pemetrexed is effective in preventing gefitinib resistance; the application of intermittent treatments requires that gefitinib not be administered before pemetrexed.

MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma

“…The flow cytometer was from Beckman Coulter, Inc. (USA, California). The PC9 lung adenocarcinoma cell line with high levels of epidermal growth factor receptor (EGFR) and phospho-EGFR, as reported previously [11, 12] was used in this study. Cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 IU/ml penicillin, and 100 IU/ml streptomycin in a 37°C incubator with an atmosphere of 5% CO 2 .…”

Continuation of gefitinib plus chemotherapy prolongs progression-free survival in advanced non-small cell lung cancer patients who get acquired resistance to gefitinib without T790M mutations

“…It was noteworthy that the clinical benefit was only observed in patients receiving pemetrexed-based combination therapy but not in other chemotherapeutic regimens. Interestingly, in cell lines and xenografts models, intermittent combination of pemetrexed and gefitinib delayed the emergence of acquired resistance and prevented the appearance of T790M mutations and EMT (33). In a randomized phase 2 trial, pemetrexed plus gefitinib significantly prolonged PFS from 10.9 to 15.8 months as compared with gefitinib alone (HR 0.68, 95% CI, 0.48-0.96; P=0.029) (34).…”

Gefitinib with pemetrexed as first-line therapy in patients with advanced nonsquamous non-small cell lung cancer with activating epidermal growth factor receptor mutations

“…In preclinical study, when PC9 and HCC827 cells were simultaneously exposed to gefitinib and pemetrexed, selection of resistant clones were not observed, suggesting that combined treatment prevented the appearance of EGFR TKI resistance (15). It was also known that the expression of thymidylate synthase was reduced with gefitinib treatment (15).…”

“…It was also known that the expression of thymidylate synthase was reduced with gefitinib treatment (15). So the enhancement of cytotoxicity when pemetrexed is added to gefitinib might suppress the small subpopulation of cells harboring T790M mutation or with the mesenchymal phenotype.…”

“…So the enhancement of cytotoxicity when pemetrexed is added to gefitinib might suppress the small subpopulation of cells harboring T790M mutation or with the mesenchymal phenotype. Preclinical studies indicated there is cell cycle dependent synergism or antagonism when combining chemotherapy and EGFR TKI, however clinical data do not support it well (10)(11)(12)(13)(14)(15)(16).…”