The Effect Of Combined Administration Of Metrexed And Sorafenib And Its Mechanism In NSCLC Cell Lines

Objective:The combination may have synergies because of different pharmocologicalmechanism between targeted drugs and chemotherapies. Thereforer, combinationadministration is a hot Issue. The effect of combined administration of multi-targetedreceptor tyrosine kinase (RTK) inhibitor (sorafenib) and chemotherapy (pemetrexed) isstill unknown. The cytotoxicity, the optimal combined modality and the mechanismsunderlying the cytotoxic synergism between sorafenib and pemetrexed for EGFRTKI-resistant NSCLC cell lines were then investigated respectively.Methods: A549(EGFR wild-type and KRAS mutation), H1975(EGFR mutation andKRAS wild-type) cell lines were treated with pemetrexed and/or sorafenib in vitro. IC50values, CI (combination index), cell cycle distribution, phospho-p44/42MAPK wereassessed respectively.Results: The cytotoxic interactions between sorafenib and pemetrexed were dosedependent in EGFR TKIs-resistant NSCLC cell lines. The administration ofpemetrexed-sorafenib sequence had a synergistic effect and an advantage oversorafenib–pemetrexed sequence and concomitant administration in both cell lines. Cellcycle analysis showed that sorafenib arrested cells mainly in G1phase while pemetrexedarrested cell mainly in S phase. Exposure to sorafenib first induced G1arrest andsubsequently prevented the cytotoxicity of S phase specific drugs, pemetrexed. Exposureto pemetrexed resulted in an increased phospho-p44/42MAPK level which was inhibitedby subsequent exposure to sorafenib. U0126,an inhibitor of the MAPK kinase alsoenhanced cytotoxicity of pemetrexed in a sequence dependent manner in TKI-resistantcell lines. Likewise, pemetrexed-activated MAPK signaling pathway was subsequentlyinhibited by U0126.Conclusions:The sequence of pemetrexed followed by sorafenib had a synergistic effectand an advantage over other sequences in EGFR TKIs-resistant NSCLC cell lines. Thesynergistic mechanism was due to sorafenib subsequently inhibiting the pemetrexed-activated, MAPK signaling pathway. The results may provide molecularevidence to support clinical treatment strategies for patients with EGFR TKIs-resistantlung cancer.