Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Geneviève Deblois, a trainee in Dr. Vincent Giguère’s group, assembled a team of researchers from six different laboratories affiliated with the GCRC to find out the mechanisms leading to resistance to this drug in HER-2 positive breast cancer.

The report published in Nature Communications shows 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. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring cell survival. Of direct clinical significance, Geneviève demonstrated that a drug inhibiting ERRα counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work thus demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.

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