دورية أكاديمية
Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer.
| العنوان: | Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer. |
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| المؤلفون: | Sethunath, V., Hu, H., de Angelis, C., Veeraraghavan, J., Qin, L., Wang, N., Simon, L., Wang, T., Fu, X., Nardone, A., Pereira, R., Nanda, S., Griffith, O.L., Tsimelzon, A., Shaw, C., Chamness, G.C., Reis-Filho, J.S., Weigelt, B., Heiser, L.M., Hilsenbeck, S.G., Huang, S., Rimawi, M.F., Gray, J.W., Osborne, C.K., Schiff, R. |
| المصدر: | Mol. Cancer Res. 17, 2318-2330 (2019) |
| بيانات النشر: | Amer Assoc Cancer Research |
| سنة النشر: | 2019 |
| المجموعة: | PuSH - Publikationsserver des Helmholtz Zentrums München |
| الوصف: | Despite effective strategies, resistance in HER2(+) breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2(+) models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2(+) breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1541-7786 1557-3125 |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/31420371; info:eu-repo/semantics/altIdentifier/wos/WOS:000494368800015; info:eu-repo/semantics/altIdentifier/isbn/1541-7786; info:eu-repo/semant; https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=57378Test; urn:isbn:1541-7786; urn:issn:1541-7786; urn:issn:1557-3125 |
| DOI: | 10.1158/1541-7786.MCR-19-0756 |
| الإتاحة: | https://doi.org/10.1158/1541-7786.MCR-19-0756Test https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=57378Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.ED462156 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15417786 15573125 |
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| DOI: | 10.1158/1541-7786.MCR-19-0756 |