An activation of <scp>LC3A</scp>‐mediated autophagy contributes to <i>de novo</i> and acquired resistance to <scp>EGFR</scp> tyrosine kinase inhibitors in lung adenocarcinoma

Nihira, Kaito; Miki, Yasuhiro; Iida, S.; Narumi, Soudai; Ono, Koji; Iwabuchi, Erina; Ise, Kazue; Mori, Kazushige; Saito, Masashi; Ebina, Masahito; Sato, Iwao; Maemondo, Makoto; Yamada-Okabe, Hisafumi; Kondo, Takashi; Sasano, Hironobu

doi:10.1002/path.4354

Cited by 46 publications

(37 citation statements)

References 55 publications

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“…A similar methylation-dependent gene silencing was also reported in lung cancer cell lines, but not in lung cancers [15]. Indeed, EGFR-TKI-resistant (epidermal growth factor receptor-tyrosine kinase inhibitor) lung cancer cells presented a decreased methylation of the promoter of MAP1LC3v1 associated with increased LC3A protein expression [18]. Inhibition of LC3A expression using siRNA also decreased LC3B-II levels and cell proliferation, whereas a 5-azadC treatment restored LC3A expression in lung cancer PC9 cells and decreased their response to EGFR-TKI.…”

Section: Negative Regulation Of Atg Genes By Dna Methylation In Cancesupporting

confidence: 72%

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Peixoto

Grandvallet

Feugeas

et al. 2019

Cells

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Although autophagy is a well-known and extensively described cell pathway, numerous studies have been recently interested in studying the importance of its regulation at different molecular levels, including the translational and post-translational levels. Therefore, this review focuses on the links between autophagy and epigenetics in cancer and summarizes the. following: (i) how ATG genes are regulated by epigenetics, including DNA methylation and post-translational histone modifications; (ii) how epidrugs are able to modulate autophagy in cancer and to alter cancer-related phenotypes (proliferation, migration, invasion, tumorigenesis, etc.) and; (iii) how epigenetic enzymes can also regulate autophagy at the protein level. One noteable observation was that researchers most often reported conclusions about the regulation of the autophagy flux, following the use of epidrugs, based only on the analysis of LC3B-II form in treated cells. However, it is now widely accepted that an increase in LC3B-II form could be the consequence of an induction of the autophagy flux, as well as a block in the autophagosome-lysosome fusion. Therefore, in our review, all the published results describing a link between epidrugs and autophagy were systematically reanalyzed to determine whether autophagy flux was indeed increased, or inhibited, following the use of these potentially new interesting treatments targeting the autophagy process. Altogether, these recent data strongly support the idea that the determination of autophagy status could be crucial for future anticancer therapies. Indeed, the use of a combination of epidrugs and autophagy inhibitors could be beneficial for some cancer patients, whereas, in other cases, an increase of autophagy, which is frequently observed following the use of epidrugs, could lead to increased autophagy cell death.

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Section: Negative Regulation Of Atg Genes By Dna Methylation In Cancesupporting

confidence: 72%

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Peixoto

Grandvallet

Feugeas

et al. 2019

Cells

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“…This is in line with previous articles, including ours, that have demonstrated the dependence of EGFR TKI-resistant lung carcinoma cells upon augmented autophagy. 6,27,28 It seems that EGFR-mutated carcinoma cells that have lost dependence on kinase activity usually exhibit enhanced autophagic flux as a compensatory mechanism for survival. Therefore, autophagy inhibition might be effective at eradicating TKI-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial–mesenchymal transition phenotype

Sakuma

Nishikiori

Hirai

et al. 2016

Laboratory Investigation

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The secondary epidermal growth factor receptor (EGFR) T790M mutation is the most prominent mechanism that confers resistance to first-or second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung cancer treatment. Although third-generation EGFR TKIs can suppress the kinase activity of T790M-positive EGFR, they still cannot eradicate EGFR-mutated cancer cells. We previously reported that a subpopulation of EGFR-mutant lung adenocarcinomas depends on enhanced autophagy, instead of EGFR, for survival, and in this study we explore another mechanism that contributes to TKI resistance. We demonstrate here that an EGFR-mutant lung adenocarcinoma cell line, H1975 (L858R+T790M), has a subset of cells that exhibits an epithelial-mesenchymal transition (EMT) phenotype and can thrive in the presence of third-generation EGFR TKIs. These cells depend on not only autophagy but also on the isomerase Pin1 for survival in vitro, unlike their parental cells. The Pin1 protein was expressed in an EGFR-mutant lung cancer tissue that has undergone partial EMT and acquired resistance to EGFR TKIs, but not its primary tumor. These findings suggest that inhibition of Pin1 activity can be a novel strategy in lung cancer treatment. Lung adenocarcinomas with an activating mutation in the epidermal growth factor receptor (EGFR) gene depend on EGFR signaling for survival and proliferation. Although most EGFR-mutant lung cancers initially respond to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, or afatinib, disease progression almost inevitably develops, on average, 1 year after the initiation of TKI therapy. The most common mechanism of acquired resistance is the secondary EGFR T790M mutation, which is found in 50-60% of resistant tumors. 1 To overcome T790M-mediated resistance, third-generation EGFR TKIs, including CO-1686 (also known rociletinib) and AZD9291, have been developed. 2,3 These drugs have potent activity against both the common EGFR mutations (inframe deletions in exon 19 and the L858R mutation in exon 21) and the T790M mutation. Recent early-phase clinical trial data demonstrated a response rate of 60% in patients with T790M-positive tumors. 4,5 Although this response rate was much higher than that of patients with T790M-negative tumors (21-29%), acquired resistance to these agents has emerged even in T790M-positive tumors. 4,5 We previously reported that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, have subpopulations of cells that display an epithelial-mesenchymal transition (EMT) phenotype and depend on enhanced autophagy, but not on EGFR activity, for survival. 6 We surmise that these EGFR-mutant cells devoid of EGFR dependency lie at the root of TKI resistance.Protein phosphorylation is a fundamental mode of intracellular signaling in many cellular processes such as proliferation and differentiation. The peptidyl-prolyl isomerase Pin1 has been identified as a regulator that catalyzes cis-trans isomerization of phosphorylated Ser/Thr-Pro motifs in a subset of phosphoryla...

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“…It is believed that autophagy promotes cell survival by recycling intracellular organelles to produce energy. Autophagic cells are highly resistant to treatment with both conventional and targeted agents, therefore providing a connection between glycolysis and drug resistance (Duffy et al ., ; Martinez Marignac et al ., ; Nihira et al ., ; Sui et al ., ). Nonetheless, prolonged autophagy and AMPK activation can also lead to additional signalling changes, which ultimately will lead to cell death.…”

Section: The Warburg Effect and Drug Resistancementioning

confidence: 99%

The Warburg effect and drug resistance

Bhattacharya

Omar

Soong

2016

British J Pharmacology

238

171

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The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development.

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An activation of LC3A‐mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma

Cited by 46 publications

References 55 publications

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial–mesenchymal transition phenotype

The Warburg effect and drug resistance

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