Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Kwon, Yoojung; Kim, Mi-Sun; Jung, Hyun Suk; Kim, Youngmi; Jeoung, Dooil

doi:10.3390/cancers11091374

Cited by 59 publications

(51 citation statements)

References 180 publications

(186 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bioinformatic approach uncovered that the 22-gene signature mainly associated with the PI3K-AKT signaling pathway, the VEGF signaling pathway, EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance, apoptosis, and ubiquitin-mediated proteolysis in LUAD. Interestingly, tons of studies have found that autophagy plays a part in the EGFR-TKI resistance of tumor cells [11–14, 35]. EGFR-TKI induces autophagy through the suppression of the PI3K/AKT/mTOR signaling pathway, which in turn saves tumor cells from the harm of EGFR-TKIs [14].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer

Liu

et al. 2019

Aging

135

147

View full text Add to dashboard Cite

Autophagy, a highly conserved cellular proteolysis process, has been involved in non-small cell lung cancer (NSCLC). We tried to develop a prognostic prediction model for NSCLC patients based on the expression profiles of autophagy-associated genes. Univariate Cox regression analysis was used to determine autophagy-associated genes significantly correlated with overall survival (OS) of the TCGA lung cancer cohort. LASSO regression was performed to build multiple-gene prognostic signatures. We found that the 22-gene and 11-gene signatures could dichotomize patients with significantly different OS and independently predict the OS in TCGA lung adenocarcinoma (HR=2.801, 95% CI=2.252-3.486, P<0.001) and squamous cell carcinoma (HR=1.105, 95% CI=1.067-1.145, P<0.001), respectively. The prognostic performance of the 22-gene signature was validated in four GEO lung cancer cohorts. Moreover, GO, KEGG, and GSEA analyses unveiled several fundamental signaling pathways and cellular processes associated with the 22-gene signature in lung adenocarcinoma. We also constructed a clinical nomogram with a concordance index of 0.71 to predict the survival possibility of NSCLC patients by integrating clinical characteristics and the autophagy gene signature. The calibration curves substantiated fine concordance between nomogram prediction and actual observation. Overall, we constructed and verified a novel autophagy-associated gene signature that could improve the individualized outcome prediction in NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

“…It was also the case with anti-EGFR treatments, as mentioned above. Autophagy inhibitors have been demonstrated to increase the sensitivity of NSCLC cells to EGFR-TKIs [35]. Moreover, the molecular interplay among apoptosis, autophagy, and proteasomal protein degradation pathway are also well documented [38, 44].…”

Section: Discussionmentioning

confidence: 99%

Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer

Liu

et al. 2019

Aging

135

147

View full text Add to dashboard Cite

show abstract

“…In this regard, our previous study has demonstrated that morusin can induce apoptosis in EGFR tyrosine kinase inhibitor-resistant NSCLC cells and treatment-naive NSCLC cells [ 20 ]. Although the current study does not focus on the chemoresistant-overcoming activity of morusin, autophagy has emerged as a potential mechanism involved in drug resistance in NSCLC [ 36 37 ]. Therefore, combined treatment with morusin and autophagy inhibitor might be effective for chemoresistant NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of cytoprotective autophagy by morusin via AMP-activated protein kinase activation in human non-small cell lung cancer cells

Park

2020

Nutr Res Pract

View full text Add to dashboard Cite

BACKGROUND/OBJECTIVES: Morusin, a marker component of Morus alba L., possesses anticancer activity. The objective of this study was to determine autophagy-inducing effect of morusin in non-small cell lung cancer (NSCLC) cells and investigate the underlying mechanism. SUBJECTS/METHODS: Autophagy induction and the expression of autophagy-related proteins were analyzed by LC3 immunofluorescence and western blot, respectively. The role of autophagy and AMP-activated protein kinase (AMPK) was determined by treating NSCLC cells with bafilomycin A1, an autophagy inhibitor, and compound C, an AMPK inhibitor. Cytotoxicity and apoptosis induction were determined by MTT assay, trypan blue exclusion assay, annexin V-propidium iodide (PI) double staining assay, and cell cycle analysis. RESULTS: Morusin increased the formation of LC3 puncta in the cytoplasm and upregulated the expression of autophagy-related 5 (Atg5), Atg12, beclin-1, and LC3II in NSCLC cells, demonstrating that morusin could induce autophagy. Treatment with bafilomycin A1 markedly reduced cell viability but increased proportions of sub-G1 phase cells and annexin V-positive cells in H460 cells. These results indicate that morusin can trigger autophagy in NSCLC cells as a defense mechanism against morusin-induced apoptosis. Furthermore, we found that AMPK and its downstream acetyl-CoA carboxylase (ACC) were phosphorylated, while mammalian target of rapamycin (mTOR) and its downstream p70S6 kinase (p70S6K) were dephosphorylated by morusin. Morusin-induced apoptosis was significantly increased by treatment with compound C in H460 cells. These results suggest that morusin-induced AMPK activation could protect NSCLC cells from apoptosis probably by inducing autophagy. CONCLUSIONS: Our findings suggest that combination treatment with morusin and autophagy inhibitor or AMPK inhibitor might enhance the clinical efficacy of morusin for NSCLC.

show abstract

“…Under physiological conditions, EGFR-activated PI3K/AKT/mTOR signaling inhibits autophagy, while in tumors received therapies this pathway contribute to resistance via activation of autophagy. However, in tumors with resistance, EGFR targeting may provide us to overcome resistance [120]. As a result, this cross-regulation mediates exosomal-induced autophagy in target cells.…”

Section: Cross-regulation By Akt/mtor Signaling Pathwaymentioning

confidence: 99%

Exosomal cargos modulate autophagy in recipient cells via different signaling pathways

et al. 2020

View full text Add to dashboard Cite

Vesicular system of mammalian cells is composed of two intracellular and extracellular vesicles systems, which contributes to the intra/intercellular communication and cellular homeostasis. These systems mediate transferring of biological molecules like proteins, nucleic acids, and lipids inside the cytoplasm, and between the cells. By the present study, authors describe molecular crosslink between exosome biogenesis and autophagy and take a certain focus on the autophagic cargos of exosomes and signaling pathways involved in exosome-induced autophagy in target cells and vice versa. Autophagy the generation of double-phospholipid vesicles, is a process that engulfs damaged proteins and organelles, share molecular similarity and function synergy with exosomes biogenesis for degradation or exocytosis of certain cargo. Exosomes, the smallest subtype of extracellular vesicles, originating from the membrane of the multivesicular body located inside cells demonstrate key roles in the intracellular and intercellular communication. Growing evidence demonstrates the interaction between exosome biogenesis and autophagy both at intertwined molecular pathways and crossbred vesicles known as amphisomes. Crosstalk between exosome biogenesis and autophagy contributes to maintain cellular homeostasis under external and internal stresses. Moreover, these processes can modulate each other via different signaling pathways. Exosomes contain autophagic cargos that induce autophagy via the cascade of molecular events in target cells, which called here exosome-induced autophagy. Taken together, crosstalk between exosome biogenesis and autophagy plays pivotal roles in cell homeostasis. Shedding light on the interaction between endomembrane systems may promote our knowledge about the relation between exosome and autophagy pathways in lysosome-related disorders against treatments; proposing a theoretical approach for therapy.

show abstract

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Cited by 59 publications

References 180 publications

Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer

Prognostic implications of autophagy-associated gene signatures in non-small cell lung cancer

Induction of cytoprotective autophagy by morusin via AMP-activated protein kinase activation in human non-small cell lung cancer cells

Exosomal cargos modulate autophagy in recipient cells via different signaling pathways

Contact Info

Product

Resources

About