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: | Xiaoyong Fu, Shixia Huang, Resel Pereira, Nicholas J. Wang, Chad A. Shaw, Jorge S. Reis-Filho, Sarmistha Nanda, Anna Tsimelzon, Agostina Nardone, Vidyalakshmi Sethunath, Rachel Schiff, Laura M. Heiser, Britta Weigelt, Lukas M. Simon, Joe W. Gray, Carmine De Angelis, Tao Wang, Mothaffar F. Rimawi, Lanfang Qin, Gary C. Chamness, Obi L. Griffith, Jamunarani Veeraraghavan, Huizhong Hu, C. Kent Osborne, Susan G. Hilsenbeck |
| المساهمون: | Sethunath, Vidyalakshmi, Hu, Huizhong, DE ANGELIS, Carmine, Veeraraghavan, Jamunarani, Qin, Lanfang, Wang, Nichola, Simon, Lukas M, Wang, Tao, Fu, Xiaoyong, Nardone, Agostina, Pereira, Resel, Nanda, Sarmistha, Griffith, Obi L, Tsimelzon, Anna, Shaw, Chad, Chamness, Gary C, Reis-Filho, Jorge S, Weigelt, Britta, Heiser, Laura M, Hilsenbeck, Susan G, Huang, Shixia, Rimawi, Mothaffar F, Gray, Joe W, Osborne, C Kent, Schiff, Rachel |
| المصدر: | Mol Cancer Res Mol. Cancer Res. 17, 2318-2330 (2019) |
| بيانات النشر: | American Association for Cancer Research (AACR), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Geranylgeranyl pyrophosphate, Receptor, ErbB-2, Farnesyl pyrophosphate, Mevalonic Acid, Antineoplastic Agents, Apoptosis, Breast Neoplasms, Mechanistic Target of Rapamycin Complex 1, Lapatinib, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Survivin, Humans, Medicine, Phosphorylation, skin and connective tissue diseases, neoplasms, Molecular Biology, business.industry, Cell growth, Trastuzumab, 030104 developmental biology, Oncology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Female, Mevalonate pathway, Growth inhibition, business, Signal Transduction, medicine.drug |
| 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. Implications: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies. |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3125 1541-7786 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a47e32d952d195af7dec86930048dfc3Test https://doi.org/10.1158/1541-7786.mcr-19-0756Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a47e32d952d195af7dec86930048dfc3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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