Abstract 432: Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader

Abstract

Abstract ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. Innate and acquired drug resistance limits the response to and durability of many cancer therapies. To identify potential mechanisms of resistance to ARV-471, we generated ARV-471-resistant MCF7 cell lines which were then characterized using DNA, RNA and functional proteomic profiling. Acquired resistance to ARV-471 was associated with downregulation of ER protein expression and signaling and upregulation of HER family (EGFR, HER2, HER3) and MAPK/AKT signaling. NRAS copy number gain was also observed, which was accompanied by increased NRAS expression. Although EGFR, HER2 and HER3 expression and activation were upregulated, no corresponding genomic alterations were observed in resistant cells. Importantly, we show that NRAS and EGFR overexpression in MCF7 cells conferred resistance to ARV-471 in vitro. Furthermore, ARV-471-resistant cells with HER pathway upregulation were sensitive to EGFR and pan-HER inhibitors. Unlike recent reports indicating the association of E3 ligase alterations with PROTAC resistance, CRBN mutations/loss were not detected, nor were ESR1 mutations. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery. Citation Format: Jessica Teh, Shannon Bessonett, Wendy Wu, Christopher Kuhlberg, Alissa Wynne, Sean Landrette, Monica Andreoli, Elizabeth Bortolon, Jennifer Pizzano, Richard Gedrich, Ian Taylor. Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 432.