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

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.