AbstractEpidermal growth factor receptor (EGFR)-activating mutations are critical factors in the development of EGFR-driven non-small-cell lung cancer (NSCLC), and molecular targeted therapies have focused on inhibiting these mutations. EGFR tyrosine kinase inhibitors (TKIs) have remarkable inhibitory effects on NSCLC with EGFR mutations.

摘要表皮生长因子受体（EGFR）激活突变是EGFR驱动的非小细胞肺癌（NSCLC）发展的关键因素，分子靶向治疗的重点是抑制这些突变。EGFR酪氨酸激酶抑制剂（TKIs）对具有EGFR突变的NSCLC具有显着的抑制作用。

However, acquired resistance limits the clinical application of EGFR-TKIs, highlighting the need for discovery of novel therapeutic strategies. 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone is a natural product derived from Garcinia xanthochymus, has shown potential anti-tumor activity, but the underlying mechanism needs further elucidation.

然而，获得性耐药限制了EGFR-TKIs的临床应用，突出了发现新治疗策略的必要性。。

In this study, we developed Ba/F3 and NIH/3T3 cells harboring EGFR L858R/T790M/C797S mutation, and then found that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exerted inhibitory effects against cells with EGFR L858R/T790M/C797S mutation. Additionally, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exhibited potent anti-tumor activity against cells harboring the triple-mutant EGFR by promoting apoptosis and inducing changes in cell cycle distribution.

在这项研究中，我们开发了携带EGFR L858R/T790M/C797S突变的Ba/F3和NIH/3T3细胞，然后发现1,4,5,6-四羟基-7,8-二丙烯基吨酮对具有EGFR L858R/T790M/C797S突变的细胞产生抑制作用。。

Furthermore, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to significantly reduce tumor growth via suppressing the phosphorylation of EGFR in tumor tissues. These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation.

此外，发现1,4,5,6-四羟基-7,8-二丙烯基吨酮通过抑制肿瘤组织中EGFR的磷酸化来显着降低肿瘤生长。这些作用与1,4,5,6-四羟基-7,8-二丙烯基吨酮与EGFR的结合有关，导致细胞外信号调节激酶（Erk）磷酸化的抑制。

In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR..

总之，我们的研究结果表明，1,4,5,6-四羟基-7,8-二烯基蒽酮可能是进一步研究和治疗具有三突变EGFR的NSCLC的潜在新候选者。。

IntroductionNon-small-cell lung cancer (NSCLC) is a malignant tumor, which is a serious threat to human health. Chemotherapy for NSCLC is only marginally effective, and the overall survival time is approximately one year1. Epidermal growth factor receptor (EGFR)-activating mutations were detected from malignant lung tissue of patients with NSCLC2.

引言非小细胞肺癌（NSCLC）是一种恶性肿瘤，严重威胁人类健康。NSCLC的化疗效果不佳，总生存时间约为一年1。从NSCLC2患者的恶性肺组织中检测到表皮生长因子受体（EGFR）激活突变。

EGFR tyrosine kinase inhibitors (TKIs) have improved overall survival to 2 years for patients with NSCLC harboring EGFR mutations and are currently being used in clinical practice3,4. Unfortunately, treatment with EGFR-TKIs results in the rapid development of resistance mutations. T790M is the most common secondary mutation and reduces sensitivity to first-generation TKIs5,6,7.

EGFR酪氨酸激酶抑制剂（TKIs）已将携带EGFR突变的NSCLC患者的总生存期提高至2年，目前正在临床实践中使用3,4。不幸的是，用EGFR-TKIs治疗会导致耐药突变的快速发展。T790M是最常见的二级突变，降低了对第一代TKIs5,6,7的敏感性。

Osimertinib has been shown to significantly suppress the activity of mutant EGFR with T790M8,9. However, the C797S mutation has been detected and is thought to induce acquired resistance in patients undergoing treatment with osimertinib10,11. Therefore, novel therapeutic strategies are urgently needed to overcome EGFR C797S mutation.Recently, EAI-045, JBJ-04-125-02, and CH7233163 were reported as effective EGFR inhibitors against the C797S mutation, but these have not been used clinically12,13,14.

Osimertinib已显示出用T790M8,9显着抑制突变EGFR的活性。然而，已经检测到C797S突变，并被认为在接受osimertinib10,11治疗的患者中诱导获得性耐药。因此，迫切需要新的治疗策略来克服EGFR C797S突变。。

Natural compounds have been widely evaluated as therapeutics in research and development, and their potential for cancer treatment has received increasing attention. In our previou study, we performed molecular interaction assays to screen 1200 natural compounds derived from plants using surface plasmon resonance (SPR) technology.

天然化合物已被广泛评估为研究和开发中的治疗剂，其治疗癌症的潜力受到越来越多的关注。在我们之前的研究中，我们使用表面等离子体共振（SPR）技术进行了分子相互作用测定，以筛选来自植物的1200种天然化合物。

1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to likely interact with EGFR, with a greater than 10 RU. The agent is a xanthone compound derived from Garcinia xanthochymus. Numerous studies demonstrated that xanthones exerted EG.

发现1,4,5,6-四羟基-7,8-二丙烯基吨酮可能与EGFR相互作用，RU大于10。该试剂是一种衍生自藤黄的吨酮化合物。大量研究表明，xanthones发挥了例如。

Data availability

数据可用性

All data generated or analyzed during this study are included in this manuscript or supplementary information.

本研究期间生成或分析的所有数据均包含在本手稿或补充信息中。

AbbreviationsEGFR:

缩写EGFR：

Epidermal growth factor receptor

表皮生长因子受体

NSCLC:

非小细胞肺癌：

Non-small-cell lung cancer

非小细胞肺癌

TKIs:

TKI：

Tyrosine kinase inhibitors

酪氨酸激酶抑制剂

Erk:

Erk公司：

Extracellular signal-regulated kinase

细胞外信号调节激酶

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Download referencesFundingThis research was funded by the Yunnan Fundamental Research Project (202201AU070177), the Project of the Yunnan Province Agricultural Basic Research Joint Foundation (202401BD070001-056) and the Yunnan Provincial Department of Education Research Project (2023J0414).Author informationAuthor notesJing Wang, Yuna Wang and Shuanggou Zhang contributed equally to this work.Authors and AffiliationsKey Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, ChinaJing Wang, Yuna Wang, Shuanggou Zhang, Yana Qu, Ruohan Zhang, Xuanjun Wang, Jun Sheng & Peiyuan SunCollege of Science, Yunnan Agricultural University, Kunming, 650201, ChinaJing Wang, Yana Qu, Ruohan Zhang & Peiyuan SunCollege of Food Science and Technology, Yunnan Agricultural University, Kunming, 650201, ChinaShuanggou ZhangAuthorsJing WangView author publicationsYou can also search for this author in.

下载参考文献资助本研究由云南省基础研究项目（202201AU070177），云南省农业基础研究联合基金会项目（202401BD070001-056）和云南省教育厅研究项目（2023J0414）资助。作者信息作者注王静，王云娜和张双沟对这项工作做出了同样的贡献。云南农业大学教育部普洱茶科学实验室的作者和附属机构，昆明，650201，王晶晶，王云娜，张双沟，瞿亚娜，张双沟，张若翰，张宣军，王俊生和孙培元，云南农业大学科学院，昆明，650201，王晶晶，瞿亚娜，张若翰和孙培元，云南农业大学食品科学与技术学院，昆明，650201，张双沟作者王晶观点作者出版物你也可以在中搜索这位作者。（笑声）。

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PubMed Google ScholarContributionsJ.S., X.W., J.W. and P.S. designed the study. Y.W., J.W., S.Z. and Y.Q. performed experiments. Y.W., J.W., R.Z. and S.Z. analyzed the data. P.S., Y.W., S.Z. and J.W. wrote the manuscript. J.S., X.W. and P.S. reviewed the manuscript. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献。S、 ，X.W.，J.W.和P.S.设计了这项研究。Y、 W.，J.W.，S.Z.和Y.Q.进行了实验。Y、 W.，J.W.，R.Z.和S.Z.分析了数据。P、 S.，Y.W.，S.Z.和J.W.撰写了手稿。J、 S.，X.W.和P.S.审查了手稿。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Xuanjun Wang, Jun Sheng or Peiyuan Sun.Ethics declarations

王宣军、盛军或孙培元。道德宣言

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Reprints and permissionsAbout this articleCite this articleWang, J., Wang, Y., Zhang, S. et al. Inhibitory effect of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone against NSCLC with L858R/T790M/C797S mutant EGFR.

转载和许可本文引用本文Wang，J.，Wang，Y.，Zhang，S。等人。1,4,5,6-四羟基-7,8-二丙烯基吨酮对L858R/T790M/C797S突变EGFR的NSCLC的抑制作用。

Sci Rep 14, 26549 (2024). https://doi.org/10.1038/s41598-024-78146-3Download citationReceived: 07 August 2024Accepted: 29 October 2024Published: 04 November 2024DOI: https://doi.org/10.1038/s41598-024-78146-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsNSCLCEGFR L858R/T790M/C797S mutation1,4,5,6-tetrahydroxy-7,8-diprenylxanthoneOsimertinib resistanceCell viability

关键词NSCLCEGFR L858R/T790M/C797S突变1,4,5,6-四羟基-7,8-二异戊二烯氧杂蒽酮Osimertinib耐药性细胞存活率