Dataset Information

Molecular mechanism of action and potential biomarkers of growth inhibition of synergistic combination of afatinib and dasatinib against gefitinib-resistant non-small cell lung cancer cells.

ABSTRACT: Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different genetic characteristics as research models to investigate the efficacy of 4 agents (gefitinib, cetuximab, afatinib and dasatinib) and their combinations. As a single agent, both afatinib and dasatinib showed more inhibition against cell proliferation than gefitinib and cetuximab. Afatinib combined with dasatinib demonstrated significantly high efficacy against 7 gefitinib-resistant NSCLC cell lines. Moreover, it reversed the resistance to the 4 studied single agents in PTEN mutated NSCLC cells. By studying the activity of EGFR, Src and their downstream signalling pathways including PI3K/PTEN/Akt, Ras/Raf/MEK/ERK, Src/FAK and JAK/Stat, we demonstrated the synergistic interaction between afatinib and dasatinib was not only due to their blockage of different signalling pathways but also the complemental inhibition of the related signalling molecules such as Stat3. We also found that the level of Src, Stat3, and MAPK may be useful biomarkers predicating synergism between afatinib and dasatinib for the treatment of gefitinib-resistant NSCLC cells.

SUBMITTER: Wang M

PROVIDER: S-EPMC5893260 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular mechanism of action and potential biomarkers of growth inhibition of synergistic combination of afatinib and dasatinib against gefitinib-resistant non-small cell lung cancer cells.

Wang Miao M Yuang-Chi Chang Alex A

Oncotarget 20180327 23

Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different geneti ...[more]

PMID: 29662665

Similar Datasets

Project description:Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase-3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.

Project description:Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.

Project description:BackgroundOvarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance.MethodsHere we target EGFR, c-Src and Met individually or in combination with carboplatin, using Gefitinib, Dasatinib and Crizotinib respectively, in a panel of carboplatin-sensitive (OVCAR-3, IGROV-1 and A2780) and carboplatin-resistant cells (SKOV-3 and EFO-21). We studied the ability of the most potent combination to induce apoptosis, regulate migration, invasion and to modulate the activation of proliferation and survival proteins.ResultsCrizotinib, Dasatinib and Gefitinib, alone or in combination with carboplatin, showed a cell-specific cytotoxic synergy in ovarian cancer cells. The Dasatinib plus Gefitinib combination was synergistic in OVCAR-3, SKOV-3 and, in IGROV-1 cells (high concentrations). This combination was unable to induce apoptosis but suppressed cell migration, invasion and the activation of EGFR, Erk, c-Src and Akt compared to single treatments.ConclusionsCombining carboplatin with kinase inhibitors lead to synergistic interactions in a cell-specific manner. Unlike platinum-based combinations, mixing Dasatinib with Gefitinib led to cytotoxic activity, inhibition of cell migration and invasion. Thus, the Dasatinib?+?Gefitinib combination presents anti-tumour properties that are superior to those of platinum-based combinations, indicating that it may well represent a promising new treatment modality to be tested in the clinic.

Dataset Information

Molecular mechanism of action and potential biomarkers of growth inhibition of synergistic combination of afatinib and dasatinib against gefitinib-resistant non-small cell lung cancer cells.

Publications

Molecular mechanism of action and potential biomarkers of growth inhibition of synergistic combination of afatinib and dasatinib against gefitinib-resistant non-small cell lung cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets