Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice

Chung, C.‐S.; Yeh, Kai-Chia; Lee, Chia-Huei; Chen, Yun-Yu; Ho, Pai-Jiun; Chang, Kuang-Hsi; Chen, Chieh-Hsin; Lai, Yiu‐Kay; Chen, Chiung‐Tong

doi:10.1016/j.phrs.2020.105183

Cited by 10 publications

(11 citation statements)

References 81 publications

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“…Regarding apoptosis analysis, we observed a death induction ranging from 10% to 60% in all treatments, which strongly correlates with the synergistic effect observed in our cytotoxicity assays. Furthermore, these findings also agree with previous studies showing apoptosis as the primary death-induced mechanism by afatinib, or metformin, both as monotherapies [ 32 , 33 , 34 ].…”

Section: Discussionsupporting

confidence: 92%

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

et al. 2022

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The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype.

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Section: Discussionsupporting

confidence: 92%

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

et al. 2022

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“…All patients signed the consent form. Inclusion criteria [6]: (1) all included patients met the corresponding inclusion criteria; (2) all included patients had a survival period of ≥12 months; (3) all included patients were 47-82 years old. Exclusion criteria [7]: (1) the included patients are pregnant women; (2) the included patients have severe mental illness and cannot complete the study independently.…”

Section: Methodsmentioning

confidence: 99%

Afatinib Targeted Therapy Affects the Immune Function and Serum Levels of EGFR and Gastrin-Releasing Peptide Precursor (pro-GRP) in Patients with Non-Small-Cell Lung Cancer (NSCLC)

Cao

Jiang

et al. 2022

Disease Markers

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Objective. This study is aimed at investigating the clinical intervention effect of afatinib targeted therapy in patients with non-small-cell lung cancer. Methods. The research object was a retrospective analysis of 86 patients with non-small-cell lung cancer who were admitted to our hospital from 1st January 2019 to 31st December 2021. The patients were divided into two groups. The patients in the two groups received conventional chemotherapy intervention, and the patients in group B received afatinib targeted therapy intervention on the basis of the treatment in group A. The clinical intervention effect, immune function, serum EGFR level, serum pro-GRP level, and incidence of adverse reactions were compared between the two groups of patients. Results. After afatinib targeted therapy intervention, the total intervention effective rate of patients in treatment group B was significantly higher than that in patients in treatment group A. Compared with the treatment group A, the CD3+, CD4+, CD8+, and CD4+/CD8+ of the treatment group were significantly upregulated. After the intervention, the serum EGFR levels of patients in treatment groups A and B were significantly decreased, and the serum EGFR levels in patients in treatment group B were significantly lower than those in patients in treatment group A. The serum pro-GRP level in group B patients was significantly decreased. The overall incidence of adverse reactions in treatment group B was significantly lower than that in treatment group A. Conclusion. Afatinib targeted therapy has a significant clinical intervention effect on patients with non-small-cell lung cancer, which not only helps to improve the immune function of patients but also effectively improves the serum EGFR and pro-GRP levels of patients.

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“…NAD + -dependency of glioma cancer cells to overcome a combined histone deacetylase and proteasome inhibitor therapy was additionally highlighted in vitro, and in most cell lines it was associated with QPRT induction [ 54 ]. QPRT induction has also been associated with in vivo acquired resistance of small cell lung carcinoma cancer cells to EGFR inhibitors [ 55 ] and as one of the four genes included in a predictive signature of chemoresistance in colorectal cancers [ 56 ]. Modulation of QPRT expression in colon carcinomas is more complex and differs according to the microsatellite stability status of the tumors.…”

Section: Dysregulation Of the Kynurenine Pathway In Cancermentioning

confidence: 99%

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

Gouasmi

Ferraro‐Peyret

Nancey

et al. 2022

Cancers

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The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success.

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Molecular profiling of afatinib-resistant non-small cell lung cancer cells in vivo derived from mice

Cited by 10 publications

References 81 publications

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

Afatinib Targeted Therapy Affects the Immune Function and Serum Levels of EGFR and Gastrin-Releasing Peptide Precursor (pro-GRP) in Patients with Non-Small-Cell Lung Cancer (NSCLC)

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

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