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Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer.
Mol. Cancer Res. 17, 2318-2330 (2019)
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Yap; Growth; Activation; Lapatinib; Promotes; Chemotherapy; Simvastatin; Reductase; Apoptosis; Transcription
ISSN (print) / ISBN 1541-7786
Journal Molecular Cancer Research
Quellenangaben Volume: 17, Issue: 11, Pages: 2318-2330
Publisher American Association for Cancer Research (AACR)
Publishing Place 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Institute(s) Institute of Computational Biology (ICB)