KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas

doi:10.1073/pnas.2303740120

科研成果详情

题名	KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas
作者	Hosaka, Kayoko 1; Andersson, Patrik 1; Wu, Jieyu 1; He, Xingkang 1,2; Du, Qiqiao 1; Jing, Xu 1; Seki, Takahiro 1; Gao, Juan 1; Zhang, Yin 3; Sun, Xiaoting 1,4; Huang, Ping 5; Yang, Yunlong 6; Ge, Minghua 7; Cao, Yihai 1
发表日期	2023-07-18
发表期刊	Proceedings of the National Academy of Sciences of the United States of America 影响因子和分区
语种	英语
原始文献类型	Journal Article ; Research Support, Non-U.S. Gov't
关键词	ANG2 Ras mutation VEGF cancer drug resistance
其他关键词	ENDOTHELIAL GROWTH-FACTOR ; TUMOR-GROWTH ; HUMAN CANCER ; ANTIANGIOGENIC THERAPY ; DISEASE PROGRESSION ; MONOCLONAL-ANTIBODY ; RAS MUTATIONS ; PHASE-I ; ANGIOGENESIS ; EXPRESSION
摘要	Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.
资助项目	European Research Council[250021];National Key R&D Program of China[2020YFC0846600];
出版者	NATL ACAD SCIENCES
ISSN	0027-8424
EISSN	1091-6490
卷号	120 期号:29
DOI	10.1073/pnas.2303740120
页数	12
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
WOS记录号	WOS:001262308700003
收录类别	PUBMED ; SCOPUS ; SCIE
URL	查看原文
PubMed ID	37428914
SCOPUSEID	2-s2.0-85164274574
自科自定义期刊分类	T3(A)类
通讯作者地址	[Cao, Yihai]Department of Microbiology,Tumor and Cell Biology,Karolinska Institute,Stockholm,171 65,Sweden
Scopus学科分类	Multidisciplinary
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/181682
专题	药学院（分析测试中心）
通讯作者	Cao, Yihai
作者单位	1.Department of Microbiology,Tumor and Cell Biology,Karolinska Institute,Stockholm,171 65,Sweden; 2.Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Zhejiang,Hangzhou,310016,China; 3.School of Pharmacology,Binzhou Medical University,Shandong,Yantai,264003,China; 4.Oujiang Laboratory,Zhejiang Lab for Regenerative Medicine,Vison and Brain Health,School of Pharmaceutical Science,Wenzhou Medical University,Wenzhou,325024,China; 5.Department of Pharmacy,Zhejiang Provincial People’s Hospital,People’s Hospital of Hangzhou Medical College,Hangzhou,310053,China; 6.Department of Cellular and Genetic Medicine,School of Basic Medical Sciences,Fudan University,Shanghai,200032,China; 7.Department of Head,Neck and Thyroid Surgery,Zhejiang Provincial People’s Hospital,People’s Hospital of Hangzhou Medical College,Hangzhou,31003,China
推荐引用方式 GB/T 7714	Hosaka, Kayoko,Andersson, Patrik,Wu, Jieyu,et al. KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas[J]. Proceedings of the National Academy of Sciences of the United States of America,2023,120(29).
APA	Hosaka, Kayoko., Andersson, Patrik., Wu, Jieyu., He, Xingkang., Du, Qiqiao., ... & Cao, Yihai. (2023). KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas. Proceedings of the National Academy of Sciences of the United States of America, 120(29).
MLA	Hosaka, Kayoko,et al."KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas".Proceedings of the National Academy of Sciences of the United States of America 120.29(2023).