A novel acquired EGFR-SEPT14 fusion confers differential drug resistance to EGFR inhibitors in lung adenocarcinoma.
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ABSTRACT:
SUBMITTER: Wang W
PROVIDER: S-EPMC10404941 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
A novel acquired <i>EGFR-SEPT14</i> fusion confers differential drug resistance to EGFR inhibitors in lung adenocarcinoma.
Wang Weidong W Lv Wang W Wang Hui H Xu Yang Y Yan Junrong J Shen Han-Ming HM Shan Liqun L Hu Jian J
Genes & diseases 20230424 6
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2015-08-12 | E-GEOD-60189 | biostudies-arrayexpress
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Project description:BackgroundThe resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer.MethodsWe compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples.ResultsOur results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma.ConclusionOur findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.
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Project description:Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.
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Project description:BackgroundIn spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats protein phosphatase (PHLPP) expression levels and the acquired resistance to EGFR TKIs in lung adenocarcinoma.ResultsHigh expression levels of PHLPP1 and PHLPP2 were detected in 69.3% and 61.3%, respectively, of patients with lung adenocarcinoma. Patients with high expression levels of PHLPP1 showed significantly longer median progression-free survival and overall survival than those with low expression levels of PHLPP1 (29 months versus 11 months, and 36 months versus 19 months respectively) (p = 0.0050 and p = 0.0052). PHLPP1, but not PHLPP2, protein expression levels was negatively correlated with p-Akt (473) and p-Erk1/2. The PHLPP1 expression levels were correlated with Progression-free survival and overall survival (p = 0.001 and p = 0.000).Materials and methodsWe recruited 75 patients with advanced lung adenocarcinoma receiving EGFR TKIs treatment. The expression levels of PHLPP1, PHLPP2, p-AKT(S473) and p-ERK1/2 were assessed using tissue immunostaining. The association of PHLPP expression levels with clinicopathological parameters and disease prognosis was analyzed.ConclusionsThis study suggests that high expression levels of PHLPP1 predict a better survival from target therapy and a longer time of acquired resistance to EGFR TKIs in patients with lung adenocarcinoma.
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