Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer Journal Article
| Authors: | Sethunath, V.; Hu, H.; De Angelis, C.; Veeraraghavan, J.; Qin, L.; Wang, N.; Simon, L. M.; 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. |
| Article Title: | Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer |
| Abstract: | 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. |
| Keywords: | chemotherapy; apoptosis; transcription; simvastatin; lapatinib; activation; growth; reductase; yap; promotes |
| Journal Title: | Molecular Cancer Research |
| Volume: | 17 |
| Issue: | 11 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-11-01 |
| Start Page: | 2318 |
| End Page: | 2330 |
| Language: | English |
| ACCESSION: | WOS:000494368800015 |
| DOI: | 10.1158/1541-7786.Mcr-19-0756 |
| PROVIDER: | wos |
| PMCID: | PMC6825570 |
| PUBMED: | 31420371 |
| Notes: | Source: Wos |
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