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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2019
- Source ID
- 10.1158/1541-7786.mcr-19-0756
Entities
People
- Agostina Nardone
- Anna Tsimelzon
- Britta Weigelt
- C. Kent Osborne
- Carmine De Angelis
- Chad Shaw
- Gary C. Chamness
- Huizhong Hu
- Jamunarani Veeraraghavan
- Joe W. Gray
- Jorge S Reis-Filho
- Lanfang Qin
- Laura M Heiser
- Lukas M. Simon
- Mothaffar F Rimawi
- Obi Griffith
- Rachel Schiff
- Resel Pereira
- Sarmistha Nanda
- Shixia Huang
- Susan Hilsenbeck
- Tao Wang
- Vidyalakshmi Sethunath
- Xiaoyong Fu
Organizations
- American Association for Cancer Research
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Helmholtz Zentrum München
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- The Breast Cancer Research Foundation
- United States Department of Defense