RNA methyltransferase METTL3 induces intrinsic resistance to gefitinib by combining with MET to regulate PI3K/AKT pathway in lung adenocarcinoma

Targeting multiple cellular populations is of high therapeutic relevance for the tackling of solid tumors heterogeneity. Herein, the ability of pegylated and pH-sensitive liposomes, functionalized with the nucleolin-binding F3 peptide and containing doxorubicin (DXR)/C6-ceramide synergistic combination, to target, in vitro, ovarian cancer, including ovarian cancer stem cells (CSC), was assessed. The underlying molecular mechanism of action of the nucleolin-mediated intracellular delivery of C6-ceramide to cancer cells was also explored. The assessment of overexpression of surface nucleolin expression by flow cytometry was critical to dissipate differences identified by Western blot in membrane/cytoplasm of SKOV-3, OVCAR-3 and TOV-112D ovarian cancer cell lines. The former was in line with the significant extent of uptake into (bulk) ovarian cancer cells, relative to non-targeted and non-specific counterparts. This pattern of uptake was recapitulated with putative CSC-enriched ovarian SKOV-3 and OVCAR-3 sub-population (EpCAMhigh/CD44high). Co-encapsulation of DXR:C6-ceramide into F3 peptide-targeted liposomes improved cytotoxic activity relative to liposomes containing DXR alone, in an extent that depended on the intrinsic resistance to DXR and on the incubation time. The enhanced cytotoxicity of the targeted combination was mechanistically supported by the downregulation of PI3K/Akt pathway by C6-ceramide, only among the nucleolin-overexpressing cancer cells presenting a basal p-Akt/total Akt ratio lower than 1.

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Prediction of the VeriStrat test in first-line therapy of pemetrexed-based regimens for advanced lung adenocarcinoma patients

10.21203/rs.3.rs-41000/v3 ◽

2020 ◽

Author(s):

Bo Jia ◽

Zhi Dong ◽

Di Wu ◽

Jun Zhao ◽

Meina Wu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Progression Free Survival ◽

Intrinsic Resistance ◽

First Line ◽

Free Survival ◽

First Line Therapy ◽

Bevacizumab Treatment ◽

Nsclc Patients ◽

The Relationship ◽

Poor Efficacy

Abstract Background：Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. Methods：This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. Results：Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P<0.001) than VS-P patients. In addition, the partial response (PR) rate was higher in the VS-G group than that in the VS-P group (46.7% vs 25.0%, P=0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G group than that in the VS-P group regardless of whether patients received chemotherapy alone or chemotherapy plus bevacizumab. Conclusions：Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

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Prediction of veristrat test in first-line therapy of pemetrexed based regimen for advanced lung adenocarcinoma patients

10.21203/rs.3.rs-41000/v2 ◽

2020 ◽

Author(s):

Bo Jia ◽

Zhi Dong ◽

Di Wu ◽

Jun Zhao ◽

Meina Wu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Progression Free Survival ◽

Intrinsic Resistance ◽

First Line ◽

Free Survival ◽

First Line Therapy ◽

Bevacizumab Treatment ◽

Nsclc Patients ◽

The Relationship ◽

Poor Efficacy

Abstract Background: Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcome on pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aim to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. Methods: This study retrospectively analyzed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. Results: Plasma samples from these patients were analyzed using VS and classified as Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacuzumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression free survival (PFS) (Unreached vs. 4.2 months; P＜0.001) than VS-P patients. Besides, partial response (PR) rate was higher in VS-G than that in VS-P group (46.7% vs 25.0%, P=0.212). Subgroup analysis showed that PFS was also significantly longer in the VS-G than that in VS-P group no matter for patients received chemotherapy alone or chemotherapy plus bevacizumab.Conclusions: Our study indicates that VS could be considered as a novel and valid method to predicit efficacy of pemetrexed based therapy and identify a subset of advanced lung adenocarcinoma patients who have intrinsic resistance to pemetrexed based regimen.

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LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway

Bioscience Reports ◽

10.1042/bsr20180999 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 11

Author(s):

Chunfeng Liu ◽

Lei Ren ◽

Jun Deng ◽

Songping Wang

Keyword(s):

Lung Adenocarcinoma ◽

Cell Lines ◽

Diagnosis And Treatment ◽

Akt Pathway ◽

Migration And Invasion ◽

In Vivo Experiments ◽

Tumor Growth And Metastasis ◽

Phosphoinositide 3 Kinase

Abstract Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion in vitro, and the in vivo experiments illustrated that its knockdown inhibited tumor growth and metastasis. What was more, we discovered that phosphoinositide 3-kinase and AKT (PI3K/AKT) pathway was activated both in LAD tissues and cell lines but inactivated under TP73-AS1 silence. Moreover, the activation of this pathway could rescue the inhibitory effects of TP73-AS1 suppression on LAD cellular processes partially. These data suggested that TP73-AS1 served as an oncogene in LAD partially through activating PI3K/AKT pathway and it could be a potential target for diagnosis and treatment of LAD.

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