دورية أكاديمية
Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer
| العنوان: | Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer |
|---|---|
| المؤلفون: | Zhang, Haisheng, Schaefer, Antje, Wang, Yichen, Hodge, Richard G., Blake, Devon R., Diehl, J. Nathaniel, Papageorge, Alex G., Stachler, Matthew D., Liao, Jennifer, Zhou, Jin, Wu, Zhong, Akarca, Fahire G., de Klerk, Leonie K., Derks, Sarah, Pierobon, Mariaelena, Hoadley, Katherine A., Wang, Timothy C., Church, George, Wong, Kwok Kin, Petricoin, Emanuel F., Cox, Adrienne D., Lowy, Douglas R., Der, Channing J., Bass, Adam J. |
| المصدر: | Zhang , H , Schaefer , A , Wang , Y , Hodge , R G , Blake , D R , Diehl , J N , Papageorge , A G , Stachler , M D , Liao , J , Zhou , J , Wu , Z , Akarca , F G , de Klerk , L K , Derks , S , Pierobon , M , Hoadley , K A , Wang , T C , Church , G , Wong , K K , Petricoin , E F , Cox , A D , Lowy , .... |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | psy, lang |
| الوصف: | Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOA Y42C , the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOA Y42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOA Y42C exhibits impaired Y42C GTP hydrolysis and enhances interaction with its effector ROCK. RHOA mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP–TAZ, PI3K–AKT, and β-catenin. RHOA Y42C murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled with sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers. SIGNIFICANCE: The functional significance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOA Y42C mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and define how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://research.vumc.nl/en/publications/e9388565-7c02-4524-91bc-4da5998ddebeTest |
| الإتاحة: | https://doi.org/10.1158/2159-8290.CD-19-0811Test https://research.vumc.nl/en/publications/e9388565-7c02-4524-91bc-4da5998ddebeTest |
| حقوق: | undefined |
| رقم الانضمام: | edsbas.A39D8069 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |