scholarly journals SCAMP3 is a mutant EGFR phosphorylation target and a tumor suppressor in lung adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Abhilash Venugopalan ◽  
Matthew Lynberg ◽  
Constance M. Cultraro ◽  
Khoa Dang P. Nguyen ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Mutant Egfr

scholarly journals Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

2020 ◽  
Author(s):  
Giorgia Foggetti ◽  
Chuan Li ◽  
Hongchen Cai ◽  
Jessica A. Hellyer ◽  
Wen-Yang Lin ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Putative Tumor Suppressor ◽  
Lung Adenocarcinomas ◽  
Gene Alterations

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.

scholarly journals The SARS-CoV-2 Host Cell Membrane Fusion Protein TMPRSS2 is A Tumor Suppressor and its Downregulation Promotes Antitumor Immunity and Immunotherapy Response in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhixian Liu ◽  
Zhilan Zhang ◽  
Qiushi Feng ◽  
Xiao-Sheng Wang
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Antitumor Immunity ◽  
Host Cells ◽  
Host Cell Membrane ◽  
Clinical Prognosis ◽  
In Vivo Experiments

Abstract TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains unexplored. In five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. We found that TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD dataset we collected. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. In conclusion, TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

scholarly journals Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

Oncotarget ◽  
2015 ◽  
Vol 6 (8) ◽  
pp. 6191-6202 ◽  
Author(s):  
Valentina E. Schneeberger ◽  
Yuan Ren ◽  
Noreen Luetteke ◽  
Qingling Huang ◽  
Liwei Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lung Adenocarcinoma ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Lung Tumors ◽  
Mutant Egfr

scholarly journals Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma

2017 ◽  
Vol 13 (5) ◽  
pp. 652-659 ◽  
Author(s):  
Yanxiao Wang ◽  
Ning Hou ◽  
Xuan Cheng ◽  
Jishuai Zhang ◽  
Xiaohong Tan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Lung Adenocarcinoma

321 An EGFR/ARF Cross-talk Controls the Growth of Lung Adenocarcinoma Cells With Mutant EGFR

2012 ◽  
Vol 48 ◽  
pp. S78-S79
Author(s):  
S. Gazzeri ◽  
O. Ozenne ◽  
D. Dayde ◽  
P. Perron ◽  
C. Barrial ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cross Talk ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Mutant Egfr

Concurrent somatic alterations of TP53 and RB1 in Chinese lung adenocarcinoma with or without EGFR mutations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21526-e21526
Author(s):  
JUN WANG ◽  
Gang Chen ◽  
Bicheng Zhang ◽  
Jianguo Sun ◽  
Jing Liang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Wild Type ◽  
Mutational Status ◽  
Significant Difference ◽  
Somatic Alterations ◽  
Egfr Mutant ◽  
Mutant Egfr

e21526 Background: Endothelial growth factor receptor (EGFR)-mutant lung adenocarcinoma displays diverse responses to tyrosine kinase inhibitor therapy. Concurrent somatic alterations represent different biological substantial proportion of patients with EGFR mutations and impacts their prognosis. Methods: We conducted this retrospective study to clarify the comprehensive concurrent genetic alterations of TP53 and RB1 and tumor mutational burden (TMB) in 712 EGFR-mutant or EGFR-wild type lung adenocarcinoma by next generation sequencing-based gene panel tests. Results: EGFR was the most frequently mutated gene altered in 58.0% (413/712) of lung adenocarcinoma, followed by TP53 altered in 56.7%, KRAS altered in 13.3%, and RBM10 altered in 11.2% of all patients. Concurrent genetic alteration of TP53 and RB1 is more likely to be found in EGFR-mutant patients than in EGFR-wild type patients, with a frequency of 11.4% (45/413) and 4.3% (13/299), respectively (p = 0.003). However, the frequency of TP53 and RB1 concurrent alteration was similar in lung cancer with sensitive EGFR mutation compared to those with non-sensitive mutation (10.5% versus 11.6%). TP53 mutation was most frequently found in patients with RB1 mutation (58/61), irrespective of EGFR mutational status. Furthermore, significant difference was found regarding median TMB in patients with mutant EGFR compared to those with non-mutant EGFR (3.8 versus 4.3; p < 0.001). Median TMB was higher for patients with TP53 and RB1 concurrent alteration than those without concurrent alteration in all patients (5.4 versus 4.3, p = 0.018). Conclusions: Our data showed that high prevalence of concurrent somatic alterations of TP53 and RB1 genes among lung adenocarcinoma patients with EGFR mutations, which might help understand several key biological processes and develop potential therapeutic strategies.

scholarly journals Activation of p53/miR-34a Tumor Suppressor Axis by Chinese Herbal Formula JP-1 in A549 Lung Adenocarcinoma Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Chih-Jung Yao ◽  
Jyh-Ming Chow ◽  
Pei-Chun Lin ◽  
Tsai-Shu Hu ◽  
Hui-Ching Kuo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Inhibitory Effect ◽  
Herbal Formula ◽  
Apoptosis Resistance ◽  
Mesenchymal Transition ◽  
Chinese Herbal Formula ◽  
Chinese Herbal ◽  
Adenocarcinoma Cells

Lung cancer is the leading cause of cancer death worldwide; the most common pathologic type is lung adenocarcinoma (LADC). In spite of the recent progress in targeted therapy, most LADC patients eventually expired due to the inevitable recurrence and drug resistance. New complementary agent with evidence-based molecular mechanism is urgently needed. MiR-34a is an important p53 downstream tumor suppressor, which regulates apoptosis, cell-cycle, EMT (epithelial mesenchymal transition), and so forth. Its expression is deficient in many types of cancers including LADC. Here, we show that a Chinese herbal formula JP-1 activates p53/miR-34a axis in A549 human LADC cells (p53 wild-type). Treatment with JP-1 induces p53 and its downstream p21 and BAX proteins as well as the miR-34a, resulting in growth inhibition, colony formation reduction, migration repression, and apoptosis induction. Accordingly, the decreases of miR-34a downstream targets such as CDK6, SIRT1, c-Myc, survivin, Snail, and AXL were observed. Moreover, JP-1 activates AMPKα and reduces mTOR activity, implying its inhibitory effect on the energy-sensitive protein synthesis and cell proliferation signaling. Our results show that JP-1 activates p53/miR-34a tumor suppressor axis and decreases proteins related to proliferation, apoptosis resistance, and metastasis, suggesting its potential as a complementary medicine for LADC treatment.

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