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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.

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Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas.
Department of Biomedical Engineering and OHSU Center for Spatial Systems Biomedicine, Portland, Oregon.
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas.
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.


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.

[Available on 2020-05-01]

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