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Sethunath, V.* ; Hu, H.* ; de Angelis, C.* ; Veeraraghavan, J.* ; Qin, L.* ; Wang, N.* ; Simon, L. ; 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.* ; Hilsenbeck, S.G.* ; Huang, S.* ; Rimawi, M.F.* ; Gray, J.W.* ; Osborne, C.K.* ; Schiff, R.*

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

Mol. Cancer Res. 17, 2318-2330 (2019)

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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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