Overcoming therapy resistance in EGFR-mutant lung cancer

Nature Cancer, Journal Year: 2021, Volume and Issue: 2(4), P. 377 - 391

Published: April 15, 2021

Language: Английский

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Emerging strategies to overcome resistance to third-generation EGFR inhibitors

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 15, 2022

Abstract Epidermal growth factor receptor (EGFR), the for members of epidermal family, regulates cell proliferation and signal transduction; moreover, EGFR is related to inhibition tumor proliferation, angiogenesis, invasion, metastasis, apoptosis. Therefore, has become an important target treatment cancer, including non-small lung head neck breast glioma, cervical bladder cancer. First- third-generation inhibitors have shown considerable efficacy significantly improved disease prognosis. However, most patients develop drug resistance after treatment. The challenge overcoming intrinsic acquired in primary recurrent cancer mediated by mutations thus driving search alternative strategies design new therapeutic agents. In view inhibitors, understanding intricate mechanisms will offer insight development more advanced targeted therapies. this review, we discuss molecular review recent resistance, challenges, future directions.

Language: Английский

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Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Cancers, Journal Year: 2021, Volume and Issue: 13(19), P. 4926 - 4926

Published: Sept. 30, 2021

Non-small cell lung cancer (NSCLC) is the most common in world. Activating epidermal growth factor receptor (

Language: Английский

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Targeting EGFR in melanoma – The sea of possibilities to overcome drug resistance

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2022, Volume and Issue: 1877(4), P. 188754 - 188754

Published: June 27, 2022

Melanoma is considered one of the most aggressive skin cancers. It spreads and metastasizes quickly intrinsically resistant to conventional chemotherapeutics, thereby presenting a challenge researchers clinicians searching for effective therapeutic strategies treat patients with melanoma. The use inhibitors mutated serine/threonine-protein kinase B-RAF (BRAF), e.g., vemurafenib dabrafenib, has revolutionized melanoma chemotherapy. Unfortunately, response these drugs lasts limited time due development acquired resistance. One proteins responsible this process epidermal growth factor receptor (EGFR). In review, we summarize role EGFR signaling in multidrug resistance melanomas discuss possible applications overcome drug cells during therapy.

Language: Английский

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Tackling Osimertinib Resistance in EGFR-Mutant Non–Small Cell Lung Cancer

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(18), P. 3579 - 3591

Published: April 24, 2023

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation TKI osimertinib. However, invariably, all patients will experience disease progression this therapy mainly due to adaptation cells through primary or secondary molecular mechanisms resistance. comprehension and access tissue cell-free DNA next-generation sequencing have fueled development innovative therapeutic strategies prevent overcome resistance osimertinib clinical setting. Herein, we review biological implications ongoing

Language: Английский

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Identification of Novel Fourth-Generation Allosteric Inhibitors Targeting Inactive State of EGFR T790M/L858R/C797S and T790M/L858R Mutations: A Combined Machine Learning and Molecular Dynamics Approach

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Targeted therapy with an allosteric inhibitor (AIs) is important area of research in patients epidermal growth factor receptor (EGFR) mutations. Current treatment nonsmall cell lung cancer EGFR mutations using orthosteric inhibitors faces challenges like resistance and stopping over phosphorylation. Notably AIs have been introduced to overcome this increase inhibitory potency that binds pockets other than the ATP-binding site (orthosteric site). Recently, fourth-generation AIs, EAI045, discovered potently selectively inhibit various but limited antiproliferative effects absence antibody cetuximab. The purpose work identify nontoxic, potent small through screening pipelines explore their molecular mechanism. In discovery structural similarity search, high-throughput virtual screening, machine learning-guided QSAR modeling, several candidates were identified. Machine learning was employed guide model based on 2D descriptors DFT-derived quantum chemical followed by a PCA reduction technique, which enabled prediction biological activity (IC50) screened drugs against such as T790M/L858R/C797S T790M/L858R. addition, multinanosecond (ns) microsecond (μs) classical dynamics (MD) simulations run protein-ligand binding complex check stability for T790M/L858R lower IC50 higher docking score compounds. mechanics generalized Boltzmann surface (MM/GBSA) calculation revealed five hit molecules T790M/C797S/L858R two had high affinity. results corroborated further MM/GBSA employing normal-mode analysis entropy method perform additional screening. Furthermore, compounds' efficacy confirmed path-dependent ligand unbinding free energy techniques Jarzynski averaged profiles obtained from adaptive steered MD, relative residence time, umbrella sampling simulations, compared reference inhibitor. However, path-independent alchemical approaches streamlined perturbation estimator 2 (BFEE2) validate These findings pave way identification novel potential require experimental validation.

Language: Английский

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Mechanisms and Future of Non-Small Cell Lung Cancer Metastasis

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Nov. 11, 2020

Lung cancer, renowned for its fast progression and metastatic potency, is rising to become a leading cause of death globally. It has been long observed that lung cancer particularly ept in spawning distant metastasis at early stages, it can readily colonize virtually any human organ. In recent years, research have shed light on why endowed with exceptional ability metastasize. this review, we will take comprehensive look the current metastasis, including molecular pathways, anatomical features genetic traits make intrinsically metastatic, as go from cancer's general potential particular mechanisms multiple organs. We highly concerned about advanced discovery development indicating importance specific gene mutations, heterogeneity or biomarker discovery, discussing opportunities challenges. also introduce some treatments targets certain strategies non-small cell cancer(NSCLC). Advances made these regards could be critical our knowledge base metastasis.

Language: Английский

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Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 245, P. 114889 - 114889

Published: Oct. 29, 2022

Language: Английский

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In silico and in vitro evaluation of novel carbothioamide-based and heterocyclic derivatives of 4-(tert-butyl)-3-methoxybenzoic acid as EGFR tyrosine kinase allosteric site inhibitors

Results in Chemistry, Journal Year: 2024, Volume and Issue: 7, P. 101329 - 101329

Published: Jan. 1, 2024

Cancer is an elaborate sequence of disease grades that include uncontrolled cell growth and division, invasion, metastasis. Overexpression the epidermal factor receptor (EGFR) causes abnormal signal transduction directly linked to cancer development. Most EGFR tyrosine kinase inhibitors (TKIs) are ATP-competitive frequently cause mutations or chemoresistance. Therefore, targeting TK allosteric site has become a highly sought after treatment strategy. Ten new derivatives 4-(tert-butyl)-3-methoxybenzoic acid containing carbothioamide (compounds 3a-e), triazole 4a-d) oxadiazole (compound 5) moieties were designed as deduced in silico. The structures these characterized by chemical spectroscopic methods (ATR-FTIR, 1HNMR, 13CNMR HRESI-MS). According molecular docking studies, compounds 3e 3d showed highest scores (ΔG), which was confirmed dynamic (MD) simulation studies. synthesized derivatives, specifically 3e, exhibited favorable pharmacokinetic profile. In vitro, newly evaluated for their cytotoxicity against A549 (lung adenocarcinoma), HepG2 (hepatocellular carcinoma), HCT-116 (colorectal) lines via MTT assay, flow cytometry, RT-PCR, immunoblotting, inhibition assay. results compound cytotoxic three tested lines, achieving lowest IC50 concentration cells. Compound caused cycle arrest at G2/M phase induction ER-mediated apoptosis pathway. silico vitro antitumor activity findings demonstrated it promising inhibitor.

Language: Английский

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Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Biomolecules & Therapeutics, Journal Year: 2021, Volume and Issue: 30(1), P. 19 - 27

Published: June 2, 2021

Epidermal growth factor receptor (EGFR) is a tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast and head neck cancer. Mutations L858R exon 21, 19 truncation (Del19), 20 insertions, others are responsible for aberrant activation of EGFR NSCLC. First-generation inhibitors (TKIs) gefitinib erlotinib have clinical benefits EGFR-sensitive (L858R Del19) NSCLC patients. However, after 10-12 months treatment with these inhibitors, secondary T790M mutation at the gatekeeper position domain was identified, which limited benefits. Second-generation irreversible (afatinib dacomitinib) were developed to overcome this mutation. their lack selectivity toward wild-type compromised due serious adverse events. Recently third-generation TKIs (osimertinib lazertinib) selective driving mutations mutation, while sparing wildtype activity. The latest studies concluded that efficacy also by additional acquired mutations, including C797S, key residue cysteine forms covalent bonds inhibitors. Because second- thirdgeneration they not effective against C797S containing triple (Del19/T790M/C797S L858R/T790M/C797S). Therefore, there an urgent unmet medical need develop next-generation selectively inhibit via non-irreversible mechanism.

Language: Английский

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