APOPTOSIS
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2026
·Vol. 31
·期 6
·158
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IF 9
Zhen Shuman,Gao Yifan,Wang Jiaqi,Ren Jingyi,Pei Huanting,Yin Danjing,Deng Yandong
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major clinical challenge in non-small cell lung cancer. Emerging evidence indicates that metabolic reprogramming and epigenetic alterations contribute to drug resistance, particularly through the evasion of ferroptosis, a regulated form of cell death characterised by lipid peroxidation. This study investigated the role of lactate-associated histone modifications in driving EGFR-TKI resistance. Resistant lung adenocarcinoma tissues and cell lines were analysed using transcriptomics, Cleavage Under Targets and Tagmentation (CUT&Tag) profiling, and biochemical assays. Glycolytic activity, lactate accumulation, and ferroptosis-related lipid peroxidation were assessed, followed by genetic and pharmacological interventions and in vivo xenograft validation. Resistant cells exhibited enhanced glycolysis and lactate accumulation, with pathway analyses highlighting ferroptosis evasion as a key resistance-associated process. Consequently, histone H4 lysine 8 lactylation (H4K8la) was significantly elevated in resistant tissues and cells. Mechanistically, H4K8la was enriched at transcription start sites, particularly at the promoter of aldo-keto reductase family 1 member C1 (AKR1C1). This epigenetic modification profoundly suppressed ferroptosis and promoted drug resistance. Disrupting this H4K8la-AKR1C1 defence axis restored lipid peroxidation, increased ferroptotic sensitivity, and resensitised resistant cells to EGFR-TKIs, as confirmed in vivo. These findings reveal a novel lactate-driven epigenetic mechanism that orchestrates ferroptosis escape and EGFR-TKI resistance, offering a promising therapeutic strategy to overcome treatment failure.
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Materials Today Bio
·
2026
·
IF 11
Fangying Zheng,Yanyun Su,Xianbin Sun,Ding Tan,Ya Wang,Xiumei Li,Yu Gao
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are primary treatments for EGFR-mutated non-small cell lung cancer (NSCLC), but acquired resistance limits efficacy. To address this challenge, we developed CsO/IGA, a multifunctional nanoplatform combining osimertinib (AZD9291) with an indocyanine green-gadolinium (ICG-Gd) probe via oleanolic acid (OA)-modified chitosan encapsulation, integrating fluorescence/magnetic resonance imaging (FLI/MRI) with chemo-phototherapy and tumor microenvironment (TME) modulation. CsO/IGA (∼100 nm) demonstrated excellent stability and generated both singlet oxygen and hyperthermia under 808 nm irradiation. The nanoplatform exerted efficient anti-cancer effects to overcome resistance through reactive oxygen species induction, mitochondrial membrane potential reduction, and EGFR/phosphorylated EGFR downregulation in sensitive and resistant NSCLC cells. Notably, the OA component suppressed cancer-associated fibroblasts and α-smooth muscle actin expression, remodeling the TME to enhance tumor penetration. In vivo studies confirmed tumor-specific accumulation and deep penetration, FLI/MRI capability, and superior antitumor efficacy through chemo-phototherapy synergy. This work presents a promising OA-integrated theranostic strategy integrating targeted therapy, phototherapy, TME modulation, and diagnostic imaging for overcoming EGFR-TKI resistance in NSCLC.
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Molecular Cancer
·
2022
·Vol. 21
·期 1
·1-17
·
IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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JOURNAL OF MEDICINAL CHEMISTRY
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2025
·
IF 6.8
Yuying Wang,Quanwei Yu,Xiongqi Yang,Lingling Ma,Ridong Huang,Hai Chen,Zhonghua Jiang,Zhenru Wu,Chengyong Wu,Xuemei Deng,Jing Wang,Weimin Li,Yang He
The tertiary C797S mutation in the EGFR tyrosine kinase domain disrupts osimertinib binding, driving resistance in NSCLC. We designed a series of novel diaminopyrimidine derivatives to establish the interaction with Ser797. H8b potently inhibited EGFRL858R/T790M/C797S kinase with an IC50 of 3.86 nM (30-fold lower than osimertinib) and suppressed both double mutant NCI-H1975 and triple mutant H1975-M3 cells with IC50s of 0.03 μM and 0.57 μM (14- and 11-fold reductions over osimertinib, respectively). Cocrystal X-ray analysis revealed that H8b forms a “two-point tethering” in the ATP pocket with a hydrogen bond between its dichloropropionamide oxygen and Ser797, complemented by a hydrogen bond between terminal N of the piperazine ring and Phe795. Mechanistically, H8b suppressed EGFR phosphorylation and downstream AKT, STAT3, and MAPK signaling, inhibiting proliferation, invasion, and migration. In vivo, H8b achieved 71.15% tumor inhibition in H1975-M3 xenografts. This study identifies H8b as a promising EGFR-TKI overcoming C797S-mediated resistance.
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BRITISH JOURNAL OF CANCER
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2026
·
IF 7.8
Zhao Kun,Zhang Jian,Wang Ran,Wang Bin,Ye Dongfan,Huang XiaoOu,Qiu Lingxiao,Duan Yi,Xu Zhi
Background EGFR-tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with non-small cell lung cancer (NSCLC); however, drug resistance limits their long-term efficacy. The role of STAT3 signaling in EGFR-TKI resistance is not completely understood. Methods Using immunohistochemistry, we assessed changes in STAT3 phosphorylation levels in NSCLC before and after EGFR-TKIs treatment. Through gene editing and transcriptome sequencing experiments, we investigated the mechanism by which STAT3 signaling mediates drug resistance. We conducted cell proliferation and nude mice tumorigenesis experiments to verify whether STAT3 inhibitors enhanced the anti-tumor effect of EGFR-TKIs on NSCLC. Results We found that inhibition of the MAPK pathway by EGFR-TKIs triggers the rapid activation of STAT3 in NSCLC. RNA-seq analysis and cellular experiments confirmed that STAT3 regulates the expression of stemness markers, which contribute to drug resistance. Cancer stemness maintenance depends on telomerase. We found that STAT3 also mediates NSCLC resistance by regulating telomerase expression. Finally, we demonstrated in both cellular and animal models that icaritin, an anti-hepatocellular carcinoma agent, significantly potentiates the anti-tumor efficacy of EGFR-TKIs against NSCLC by inhibiting STAT3 activation. Conclusions The combination of EGFR-TKIs and STAT3 inhibitors has the potential to be a better therapeutic strategy for EGFR-mutant NSCLC than EGFR-TKI monotherapy. The alternative text for this image may have been generated using AI.
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BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Menglong Zhao,Danqing Wu,Weiqian Qiu,Hongchen Zhang,Min Chen,Haixia Zhou,Xiaoxia Ye,Zhong Han,Xiangchao Shi
4-anilinoquinazoline scaffold, a key structure in the development of EGFR-TKI anticancer drugs such as Gefitinib and Erlotinib, continues to drive advancements in non-small cell lung cancer (NSCLC) therapy. In this study, we synthesized a series of novel derivatives ( B3–B11 ). Structure-activity relationship (SAR) analysis revealed that electron-donating groups para-substituted at the 4-anilino position significantly enhanced antiproliferative activity. Notably, B10 incorporating an acrylamide group at the 4-anilino position demonstrated the most potent activity against NSCLC, with an IC 50 of 1.28 μM in A549 cells, nearly six times more effective than Gefitinib (7.81 μM). Acute toxicity studies confirmed that B10 is safe at doses below 50 mg/kg. In vivo studies using an A549 xenograft model showed a 46 % tumor growth inhibition (TGI) with B10 (25 mg/kg), surpassing the 21 % inhibition of Gefitinib at the same dose. Mechanistic studies revealed that B10 inhibited the AKT/GSK-3β/β-catenin signaling pathway, downregulating Wnt target genes (c-Myc, c-Jun), and reduced COX2 expression and IL-8 levels, showcasing its dual anti-inflammatory and antitumor effects. These results position B10 as a promising NSCLC therapeutic candidate, combining potent efficacy with a favorable safety profile, and enhance our understanding of the SAR and mechanism of action of 4-anilinoquinazoline derivatives.
研究领域:
肿瘤学
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药理学
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分子生物学
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药物化学
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