Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer

Vidyalakshmi Sethunath, Huizhong Hu, Carmine De Angelis, Jamunarani Veeraraghavan, Lanfang Qin, Nicholas Wang, Lukas M. Simon, Tao Wang, Xiaoyong Fu, Agostina Nardone, Resel Pereira, Sarmistha Nanda, Obi L. Griffith, Anna Tsimelzon, Chad Shaw, Gary C. Chamness, Jorge S. Reis-Filho, Britta Weigelt, Laura M. Heiser, Susan G. HilsenbeckShixia Huang, Mothaffar F. Rimawi, Joe W. Gray, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)2318-2330
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number11
DOIs
StatePublished - Jan 1 2019

Fingerprint Dive into the research topics of 'Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer'. Together they form a unique fingerprint.

  • Cite this

    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., ... Schiff, R. (2019). Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer. Molecular Cancer Research, 17(11), 2318-2330. https://doi.org/10.1158/1541-7786.MCR-19-0756