EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR

Jo, Ukhyun; Park, Kyong Hwa; Whang, Young Mi; Sung, Jae Sook; Won, Nam Hee; Park, Jong Kuk; Kim, Yeul Hong

doi:10.18632/oncotarget.1711

Cited by 52 publications

(47 citation statements)

References 42 publications

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“…We have demonstrated that the Rab25 amplicon and Rab25 expression is associated with a worsened outcome in ovarian cancer and increased the aggressiveness of a subset of breast cancer cell lines [32, 33]. Further, increased Rab25 is associated with poor patient outcome in lung [34], clear cell renal [35] and bladder [28] cancers likely through effects on metastatic pathways [36]. Mechanistically Rab25 decorated vesicles transport integrins [37, 38], PI3K [39], and EGFR [7] facilitating aggressive tumor growth and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT

et al. 2016

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The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.

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Section: Introductionmentioning

confidence: 99%

Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT

et al. 2016

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“…Tumor cells that are initially sensitive to gefitinib may eventually lose sensitivity due to the emergence of acquired resistance [44]. Alternative mechanisms are currently being explored aimed to overcome the development of gefitinib resistance in the patients of NSCLC [44, 45]. Recent studies [8, 25] show that miR-21 modulates gefitinib sensitivity.…”

Section: Resultsmentioning

confidence: 99%

Exosomal miRs in Lung Cancer: A Mathematical Model

Lai

Friedman²

2016

PLoS ONE

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Lung cancer, primarily non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths in the United States and worldwide. While early detection significantly improves five-year survival, there are no reliable diagnostic tools for early detection. Several exosomal microRNAs (miRs) are overexpressed in NSCLC, and have been suggested as potential biomarkers for early detection. The present paper develops a mathematical model for early stage of NSCLC with emphasis on the role of the three highest overexpressed miRs, namely miR-21, miR-205 and miR-155. Simulations of the model provide quantitative relationships between the tumor volume and the total mass of each of the above miRs in the tumor. Because of the positive correlation between these miRs in the tumor tissue and in the blood, the results of the paper may be viewed as a first step toward establishing a combination of miRs 21, 205, 155 and possibly other miRs as serum biomarkers for early detection of NSCLC.

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“…PICALM and AP2A2 are associated with clathrin and are thus closely involved in endocytosis, one of the three main functions enriched in SDGS genes and their PPI partners (Figure ). EGFR endocytosis can be a pathway from which to find novel therapeutic targets for lung cancer with wild‐type EGFR . An abnormality in bypass signaling pathways is another of several mechanisms of EGFR resistance to TKIs, and one of those bypass pathways involves vascular endothelial growth factor (VEGF) and its receptor, VEGFR.…”

Section: Discussionmentioning

confidence: 99%

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

Hwang

2019

Cancer Medicine

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The overall survival rates for lung cancer remain unsatisfactorily low, even for patients with biomarkers for which target therapies or immunotherapies are recommended. Better identification of at‐risk patients is needed to achieve more effective personalized treatment. Here, we derived a risk‐stratifying gene signature consisting of five genes that had the greatest differential expression by stage from lung adenocarcinoma (LUAD) transcriptomes. The new gene signature enabled survival prognosis for multiple LUAD datasets from different platforms of transcriptomics and risk stratification for patients with and without a mutation in TP53 or EGFR, with high and low levels of PD‐L1, and with and without adjuvant chemotherapy treatment. Using these evaluations, it was also shown to be more robust compared to several other gene signatures. Functional analysis of the five genes and their protein‐protein interaction partners indicated that they are functionally enriched in cell cycle, endocytosis, and EGFR regulation, which are biological processes associated with lung cancer and drug resistance. Extensive discussions on related experimental studies suggest that the five genes are novel and sensible targets for developing new drugs and/or tackling drug resistance problems for LUAD.

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EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR

Cited by 52 publications

References 42 publications

Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT

Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT

Exosomal miRs in Lung Cancer: A Mathematical Model

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

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