Abstract 2285: TGFβ Induction: An essential tumor suppressive arm of next generation SERDs in ER+ breast cancer models in vitro

Abstract Breast cancer is the most diagnosed cancer globally, with a significant need for improved treatments for the most prevalent Estrogen Receptor α (ER)-positive subtype, where ER signaling drives cell proliferation.The next-generation oral Selective ER antagonist and degrader (SERD), giredestrant, is a potent investigational agent that robustly suppresses tumor cell proliferation. However, primary and acquired resistance pose a major challenge to all endocrine therapies including oral SERDs, necessitating a deeper understanding of resistance mechanisms. In a comprehensive whole-genome CRISPR screen, we sought to identify genetic perturbations that confer a growth advantage in the presence of giredestrant. Notably, knockout of multiple TGFβ signaling components (TGFβ3, SMAD4, IPO8, TGFβR2) consistently freed ER+ cells from giredestrant-induced cell cycle arrest. We establish an unexpected autocrine mechanism: by suppressing the ER pathway, giredestrant induces the expression and signaling of the tumor suppressor TGFβ3. This induced TGFβ signaling then elevates CDKN1A (p21) levels, which precedes the inhibition of its natural target, CDK2. We demonstrate that this TGFβ→p21-|CDK2 axis is necessary for giredestrant to achieve its maximal inhibitory effect in vitro. Molecular profiling confirmed CDKN1A was among the most significantly suppressed genes when TGFβ signaling was inhibited in combination with giredestrant. Crucially, combining giredestrant and a TGFβ inhibitor led to resistance, but this was partially overcome by a combination of CDK4/6 and CDK2 inhibition. This finding shows that CDK4/6/2 blockade can bypass, in-part, the requirement for the p21 cell cycle brake. Collectively, our results reveal that giredestrant's in vitro efficacy relies on an autocrine TGFβ loop to mediate the necessary G1 arrest. The inhibition of TGFβ creates a resistance mechanism by neutralizing this essential tumor-suppressive signaling component. Citation Format: Kareem Heslop, Jackson Liang, Steffan Vartanian, Jinchu Vijay, Liang-Fu Chen, Marc Hafner, Michael Costa, Ciara Metcalfe. TGFβ Induction: An essential tumor suppressive arm of next generation SERDs in ER+ breast cancer models in vitro abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2285.