scholarly journals Targeting 14-3-3ζ overcomes resistance to EGFR-TKI in lung adenocarcinoma via BMP2/Smad/ID-1 signaling

2020 ◽  
Author(s):  
Jinfang Cui ◽  
Yang Song ◽  
Xuejiao Han ◽  
Jing Hu ◽  
Yanbo Chen ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Microarray Analysis ◽  
Kinase Inhibitor ◽  
The Cancer Genome Atlas ◽  
Egfr Mutations ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Pan Cancer

Abstract Background: 14-3-3ζ protein which acts as a putative oncoprotein has been found to promote proliferation, metastasis and chemoresistance of cancer cells in several cancers including lung adenocarcinoma (LUAD), however, its significance in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to determine 14-3-3ζ expression in pan-cancer and LUAD. 14-3-3ζ and ID1 expression was then examined in clinical LUAD samples by immunohistochemistry (IHC). Lentiviral transfection with 14-3-3ζ-specific shRNA was used to establish stable 14-3-3ζ knockdown gefitinib resistant PC9 (PC9/GR) and H1975 cell lines. The effect of 14-3-3ζ knockdown on reversing EGFR-TKI resistance was determined in vitro by CCK-8, wound healing, transwell assays and flow cytometry. A xenograft tumor model was established to evaluate the role of 14-3-3ζ in EGFR-TKI resistance. Microarray analysis results showed the multiple pathways regulated by 14-3-3ζ-shRNA. Results: In the present study, we firstly demonstrated that 14-3-3ζ expression was elevated and predicted unfavourable prognosis in pan-cancer including LUAD based on TCGA. In addition, high 14-3-3ζ expression was significantly associated with advanced T stage, TNM stage, present of lymph node metastasis and, importantly, poor treatment response to EGFR-TKI in LUAD patients with EGFR-activating mutations. 14-3-3ζ shRNA significantly sensitized EGFR-TKI-resistant human LUAD cells to gefitinib and, notably, reversed epithelial-to-mesenchymal transition (EMT). BMP signaling activation was decreased in EGFR-TKI resistant cells followed by 14-3-3ζ depletion in microarray analysis, which was further validated by Western blot analysis. Furthermore, the expression of 14-3-3ζ positively correlates with ID1 expression in human EGFR-mutant LUAD patient samples. In vivo , 14-3-3ζ shRNA and gefitinib treatment resulted in a significant reduction in the tumor burden compared to that treated with gefitinib alone. Conclusion: Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. This study might provide a potential therapeutic approach for treating LUAD patients harboring EGFR mutations.

scholarly journals Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

2020 ◽  
Author(s):  
Xu Zhang ◽  
Tapan K. Maity ◽  
Karen E. Ross ◽  
Yue Qi ◽  
Constance M. Cultraro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Egfr Mutations ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

scholarly journals S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB

Oncotarget ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 7631-7643 ◽  
Author(s):  
Po-Hao Feng ◽  
Chih-Teng Yu ◽  
Kuan-Yuan Chen ◽  
Ching-Shan Luo ◽  
Shen Ming Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tki Resistance ◽  
Egfr Tki

scholarly journals Correction: S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB

Oncotarget ◽  
2018 ◽  
Vol 9 (59) ◽  
pp. 31559-31559
Author(s):  
Po-Hao Feng ◽  
Chih-Teng Yu ◽  
Kuan-Yuan Chen ◽  
Ching-Shan Luo ◽  
Shen Ming Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tki Resistance ◽  
Egfr Tki

scholarly journals Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Jayesh Kumar Tiwari ◽  
Shloka Negi ◽  
Manju Kashyap ◽  
Sheikh Nizamuddin ◽  
Amar Singh ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Escape ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Gene Signatures ◽  
Immune Exhaustion ◽  
Cancer Types ◽  
Tcga Dataset ◽  
Pan Cancer

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p < 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p < 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Xiao Wu ◽  
Suzhi Li ◽  
Chen Kan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Feedback Loop ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Egfr Mutations ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), posing a major challenge to developing effective treatment of lung adenocarcinoma (LUAD). The strategy of combining EGFR-TKI with other synergistic or sensitizing therapeutic agents are considered a promising approach in the era of precision medicine. Moreover, the role and mechanism of SHP2, which is involved in cell proliferation, cytokine production, stemness maintenance and drug resistance, has not been carefully explored in lung adenocarcinoma (LUAD). Methods To evaluate the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 inhibition was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing was performed to explore the mechanism of SHP2 promoted stemness. Results This study demonstrated that high SHP2 expression level correlates with poor outcome of LUAD patients, and SHP2 expression is enriched in Osimertinib resistant LUAD cells. SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. SHP2 facilitates the secretion of CXCL8 cytokine from the EGFR T790M mutant LUAD cells, through a CXCL8-CXCR1/2 positive feedback loop that promotes stemness and tumorigenesis. Our results further show that SHP2 mediates CXCL8-CXCR1/2 feedback loop through ERK-AKT-NFκB and GSK3β-β-Catenin signaling in EGFR T790M mutant LUAD cells. Conclusions Our data revealed that SHP2 inhibition enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may help provide an alternative therapeutic option to enhance the clinical efficacy of osimertinib in EGFR T790M mutant LUAD patients.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Suzhi Li ◽  
Chen Kan ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Cxcl8 Secretion ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.

scholarly journals ARNTL2, an Immunoregulation-Related Prognostic Biomarker in Pan-Cancer and Lung Adenocarcinoma

2021 ◽  
Author(s):  
Gujie Wu ◽  
Wenmiao Wang ◽  
Zheng Yang ◽  
Qun Xue
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Prognostic Biomarker ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Cancer Drugs ◽  
Anti Cancer ◽  
Pan Cancer

Abstract Background ARNTL2 is a member of the PAS superfamily that promotes tumor progression. However, the role of ARNTL2 in lung adenocarcinoma (LUAD) remains unclear. The purpose of our study was to investigate the function of ARNTL2 in LUAD. Methods The expression, clinical features, and prognostic role of ARNTL2 in pan-cancer were evaluated using The Cancer Genome Atlas and Genotype-Tissue Expression data. GSEA and GSVA of ARNTL2 were performed using the R package “clusterProfiler.” The correlation between immune cell infiltration level and ARNTL2 expression was analyzed using two sources of immune cell infiltration data, including the TIMER2 and ImmuCellAI database. Finally,we analyzed the correlation between ARNTL2 and IC50 of 192 drugs. Results ARNTL2 was substantially overexpressed in LUAD and pan-cancer. High ARNTL2 expression predicted poor survival in patients with LUAD. We also found that ARNTL2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as tumor associated macrophages, cancer associated fibroblasts and Tregs. Among the 192 anti-cancer drugs, ARNTL2 expression was positively correlated with IC50 of 114 anti-cancer drugs, such as SB505124, Doramapimod, Nutlin-3a (-), Sabutoclax, AZD5991, PF-4708671, Elephantin, PRIMA-1MET, Sorafenib, Vorinostat, and MK-2206. Conclusions Our results revealed that ARNTL2 is a potential prognostic biomarker in LUAD. An elevated ARNTL2 expression indicates an immunosuppressive microenvironment, and targeted therapies against ARNTL2 have excellent potential.

scholarly journals Clinical Significance and Prognostic Value of Human Soluble Resistance-Related Calcium-Binding Protein: A Pan-Cancer Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jinguo Zhang ◽  
Jian Chen ◽  
Benjie Shan ◽  
Lin Lin ◽  
Jie Dong ◽  
...  
Keyword(s):  
Immune Cells ◽  
Calcium Binding ◽  
Drug Sensitivity ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
The Cancer Genome Atlas ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Pan Cancer

The soluble resistance-related calcium-binding protein (sorcin, SRI) serves as the calcium-binding protein for the regulation of calcium homeostasis and multidrug resistance. Although the mounting evidence suggests a crucial role of SRI in the chemotherapeutic resistance of certain types of tumors, insights into pan-cancer analysis of SRI are unavailable. Therefore, this study aimed to probe the multifaceted properties of SRI across the 33 cancer types. The SRI expression was analyzed via The Cancer Genome Atlas (TCGA) and Genotype Tissue-Expression (GTEX) database. The SRI genomic alterations and drug sensitivity analysis were performed based on the cBioPortal and the CellMiner database. Furthermore, the correlations among the SRI expression and survival outcomes, clinical features, stemness, tumor mutation burden (TMB), microsatellite instability (MSI), and immune cells infiltration were analyzed using TCGA data. The differential analysis showed that SRI was upregulated in 25 tumor types compared with the normal tissues. Aberrant expression of SRI was able to predict survival in different cancers. Further, the most frequent alteration of SRI genomic was amplification. Moreover, the aberrant SRI expression was related to stemness score, epithelial-mesenchymal-transition (EMT)-related genes, MSI, TMB, and tumor immune microenvironment in various types of cancer. TIMER database mining further found that the SRI expression was significantly correlated with the infiltration levels of various immune cells in certain types of cancer. Intriguingly, the SRI expression was negatively correlated with drug sensitivity of fluorouracil, paclitaxel, docetaxel, and isotretinoin. Our findings highlight the predictive value of SRI in cancer and provide insights for illustrating the role of SRI in tumorigenesis and drug resistance.

scholarly journals Comprehensive Analysis of The Significance of Hypoxia-Related Genes in Ovarian Cancer

2021 ◽  
Author(s):  
Wancheng Zhao ◽  
Lili Yin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Principal Component ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Pca Algorithm

Abstract Background: Hypoxia-related genes have been reported to play important roles in a variety of cancers. However, their roles in ovarian cancer (OC) have remained unknown. The aim of our research was to explore the significance of hypoxia-related genes in OC patients.Methods: In this study, 15 hypoxia-related genes were screened from The Cancer Genome Atlas (TCGA) database to group the ovarian cancer patients using the consensus clustering method. Principal component analysis (PCA) was performed to calculate the hypoxia score for each patient to quantify the hypoxic status. Results: The OC patients from TCGA-OV dataset were divided into two distinct hypoxia statuses (cluster.A and cluster.B) based on the expression level of the 15 hypoxia-related genes. Most hypoxia-related genes were expressed more highly in the cluster.A group than in the cluster.B group. We also found that patients in the cluster.A group exhibited higher expression of immune checkpoint-related genes, epithelial-mesenchymal transition-related genes, and immune activation-related genes, as well as elevated immune infiltrates. PCA algorithm indicated that patients in the cluster.A group had higher hypoxia scores than that in in the cluster.B group.Conclusions: In summary, our research elucidated the vital role of hypoxia-related genes in immune infiltrates of OC. Our investigation of hypoxic status may be able to improve the efficacy of immunotherapy for OC.

scholarly journals Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Hongli Li ◽  
Qingjie Mu ◽  
Guoxin Zhang ◽  
Zhixin Shen ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Biological Significance ◽  
Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

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