Abstract
Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.
Highlights
IntroductionDespite the initial benefits of treating human EGFR-2 (HER2)-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops
Despite the initial benefits of treating human epidermal growth factor receptor (EGFR)-2 (HER2)-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops
ERRa expression positively correlates with HER2 status and with poor prognosis in breast tumours[26,27], and we recently showed that it contributes to ERBB2-dependent mammary tumorigenesis in mice[28]
Summary
Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Proposed bypassing routes include the activation of kinases downstream of b1 integrin[8,9], stimulation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)[10,11,12,13] and enhanced autocrine mitogenic signalling[14,15,16,17,18] While these observations suggest that reactivation of RTK or of alternative signalling routes may restore the proliferative potential of lapatinib-treated breast cancer cells, the downstream effects responsible for conferring resistance to lapatinib remain unknown. EGF has been shown to induce the recruitment of ERRa to the promoter of the TFF1 gene[29], while signals from HER2 impact on ERRa transcriptional activity[30,31] These observations suggest that ERRa could participate as a downstream effector of mitogenic signals to mediate the metabolic adaptation of HER2-positive breast cancer cells and subsequently in their response to lapatinib. We explore the hypothesis that ERRa acts as an effector of mitogenic signalling responsible for metabolic adaptations of breast cancer cells and further provide evidence of its implication in the therapeutic response and resistance to the RTK inhibitor lapatinib
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