Novel considerations on EGFR-based therapy as a contributor to cancer cell death in NSCLC

Peng, Weiwei; Yao, Chengyun; Pan, Qing‐Jiang; Zhang, Zhi; Ye, Jinjun; Shen, Bo; Zhou, Guoren; Fang, Ying

doi:10.3389/fonc.2023.1120278

Cited by 8 publications

(7 citation statements)

References 93 publications

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“…Based on literatures, the blockade of EGFR signaling in malignant cells not only inhibits cell proliferation and induces apoptosis but also prevents cancer development via various mechanisms such as prevention of invasion and metastasis, and reversal of immunosuppression via inhibiting EGFR activation upregulated PD-L1 expression. [4] Our results are in consistence with the previous reports.…”

Section: Therapeutic Effects Of Drug Loaded Silk Peptide Nanoparticle...supporting

confidence: 93%

“…[ 38,39 ] ERL competes with adenosine triphosphate (ATP) for the ATP binding site within the intracellular tyrosine kinase domain of EGFR to inhibit the EGFR function, and thus impairs the EGFR activated downstream signaling pathways such as PI3K/Akt and Ras/MAPK pathways. [ 4 ] The inhibition of these pathways may result in downregulated EGFR in turn. Our results are in consistence with the previous studies.…”

Section: Resultsmentioning

confidence: 99%

“…[ 3 ] In most cases, mutations of EGFR occur in exon 19 (ex19del) and exon 21 (L858R). [ 4 ] Erlotinib (ERL), a targeted therapy drug, is widely used in cancer treatments as a tyrosine kinase inhibitor (TKI) targeting mutant EGFR. Clinically, ERL has been approved for the treatment of non‐smallcell lung cancer (NSCLC) and pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing targeted cancer therapy through multiple drug delivery by silk peptide nanoparticles

He,

Qi,

et al. 2024

Nano Select

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Targeted therapy drugs exert an essential role in precision therapy in cancer treatments. However, their therapeutic efficiency is greatly limited by the poor water solubility and low bioavailability. Herein, by using an epidermal growth factor receptor (EGFR) targeted drug, erlotinib (ERL), as a representative of targeted therapy drugs, we demonstrate silk peptide (SP) extracted from silkworm cocoons can be used as a drug carrier to co‐load curcumin (CUR) and ERL to achieve dramatically improved antitumor therapeutic efficiency. The dual‐drug loaded nanoparticles (CUR/ERL@SP) with a mean size within 150 nm show significantly enhanced cell internalization, and thus induce more effective inhibition of cancer cell growth. As compared with free drugs, CUR/ERL@SP can more efficiently downregulate the expression of EGFR and other proteins promoting tumor invasion, immunosuppression and cell fusion in EGFR mutant PC‐9 lung cancer cells. The evaluation by using the circulating malignant cells (CMCs) from a lung cancer patient further confirms that CUR/ERL@SP can more effectively inhibit EGFR expression. This study provides a convenient strategy to enhance the therapeutic efficacy of targeted therapy drugs and a facile ex vivo method for evaluating treatment outcomes in personalized therapy.

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Section: Therapeutic Effects Of Drug Loaded Silk Peptide Nanoparticle...supporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhancing targeted cancer therapy through multiple drug delivery by silk peptide nanoparticles

He,

Qi,

et al. 2024

Nano Select

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“…One of the most frequent mechanisms of gefitinib resistance is secondary EGFR mutation, such as the exon 20 T790M mutation, which is targeted by the third-generation EGFR-TKI osimertinib [ 27 ]. Besides the secondary EGFR mutations, amplification, loss, and mutation of some other cancer-related genes also contribute to gefitinib resistance, such as MET, HER2, BRAF, and PIK3CA [ 28 ]. However, the present understanding of the mechanisms of gefitinib resistance still cannot satisfy the clinical demand.…”

Section: Discussionmentioning

confidence: 99%

NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence

Zhen,

Jia,

Zhao

et al. 2024

Cell Death Discov.

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Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.

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“…Based on the rapidly evolving research environment in the 1990s, drug companies initiated projects to develop agents which blocked signaling by growth factor receptors, for example, ERBB1/EGFR, RAF-1/ B-RAF, MEK1/2 and PI3K. Within a few years, the drugs erlotinib and gefitinib were developed to block signaling by ERBB1/EGFR; the drugs sorafenib and regorafenib were developed to block signaling by RAF-1/ B-RAF; the drugs PD98059 and U0126 were developed to block MEK1/2 signaling; and the drugs wortmannin and LY294002 developed to block PI3K signaling [9][10][11][12]. Subsequently, a second generation of ERBB1/EGFR inhibitors was developed that also inhibited ERBB2/HER2, for example, lapatinib.…”

Section: Introductionmentioning

confidence: 99%

Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells

Booth,

Roberts,

Poklepovic

et al. 2023

Anti-Cancer Drugs

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Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70S6K. This collectively results in reduced protein synthesis and the induction of an endoplasmic reticulum stress response alongside autophagosome formation and autophagic flux. The rupture of autolysosomes, releasing proteases such as cathepsin B into the cytosol results in the cleavage and activation of the toxic BH3 domain protein BID which cooperates with BAX, BAK and BIM to cause mitochondrial dysfunction, leading to the release of cytochrome c and AIF, which then execute the tumor cell. For each of our two-drug combinations, we then performed additional laboratory-based studies to define the development of evolutionary resistance mechanisms, with the long-term concept of performing new three-drug clinical trials to prolong therapeutic efficacy and disease control.

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Novel considerations on EGFR-based therapy as a contributor to cancer cell death in NSCLC

Cited by 8 publications

References 93 publications

Enhancing targeted cancer therapy through multiple drug delivery by silk peptide nanoparticles

Enhancing targeted cancer therapy through multiple drug delivery by silk peptide nanoparticles

NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence

Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells

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