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Mol Cancer Res. 2019 Nov;17(11):2318-2330. doi: 10.1158/1541-7786.MCR-19-0756. Epub 2019 Aug 16.

Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer.

Author information

1
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
2
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
3
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
4
Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine, Portland, Oregon.
5
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
6
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
7
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas.
8
Department of Medicine, Baylor College of Medicine, Houston, Texas.
9
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
11
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. rschiff@bcm.edu.

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. 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.

PMID:
31420371
PMCID:
PMC6825570
[Available on 2020-05-01]
DOI:
10.1158/1541-7786.MCR-19-0756

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