克拉斯
癌症研究
血管内皮生长因子
贝伐单抗
血管生成
抗药性
血管生成素受体
结直肠癌
血管生成素
生物
血管内皮生长因子A
医学
癌症
药理学
血管内皮生长因子受体
内科学
肿瘤科
化疗
遗传学
作者
Kayoko Hosaka,Patrik Andersson,Jing‐Ming Wu,Xingkang He,Qiqiao Du,Jing Xu,Takahiro Seki,Juan Gao,Yin Zhang,Xiaoting Sun,Ping Huang,Yunlong Yang,Minghua Ge,Yihai Cao
标识
DOI:10.1073/pnas.2303740120
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.
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