The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins. [Display omitted] •FOXA1 cooperates with GRHL2 to drive resistance to endocrine therapy in breast cancer•LYPD3 is a targetable node downstream of FOXA1/GRHL2•Targeting LYPD3 and its ligand AGR2 inhibit the growth of therapy-resistant tumors Cocce et al. show that FOXA1 contributes to disease pathogenesis by cooperating with GRHL2 in endocrine therapy-resistant breast cancer. LYPD3 is identified as an actionable downstream target of FOXA1/GRHL2, and humanized antibodies against LYDP3, or its ligand AGR2, demonstrate anti-tumor efficacy in animal models of endocrine therapy-resistant breast tumors.