Abstract B044: Targeting the “undruggable” oncogene CCNE1 using a molecular glue degrader in CCNE1 amplified cancers

作者：William Tahaney, Yimao Liu, Ahmed Abdullah, Vittoria Massafra, Verena Lang, Markus Baumann, Aurelie Dubois, Arnaud Osmont, Xavier Lucas, Chao Quan, Anna Kostikova, Anna Diesslin, Freya Harvey, Christelle Bianda, Kevin Larpenteur, Katherine Jones, Anne-Cecile D’Alessandro, Carolina Perdomo Ortiz, Hervé Farine, Maciej Cabanski, Manav Korpal, Bradley DeMarco, Débora Bonenfant, Markus Warmuth, Filip Jankú, Magnus Walter, Sharon Townson, Bernhard Fasching, Simone Tortoioli, C. King, L. L. McAllister, Sofia Gkountela, B. Ranieri, Ralph Tiedt, Nina Ilic-Widlund · 发表于：Clinical Cancer Research · 年份：2026 · DOI：10.1158/1557-3265.d32026-b044 · 研究领域：Cancer research、Biology、Chemistry

Abstract Using our QuEENTM molecular glue degrader (MGD) discovery engine that integrates biochemical and cellular assays with in silico modeling, we identified and optimized MGDs that induce proteasomal degradation of cyclin E1 (CCNE1) as a therapeutic strategy for CCNE1-amplified cancers. We generated a highly selective CCNE1 degrader that spares related cyclins and other proteins. CCNE1 is a key regulator of G1/S cell-cycle progression. As the regulatory subunit of the CCNE1–CDK2 holoenzyme, it promotes RB phosphorylation, relieves RB-mediated repression, and drives proliferation. CCNE1 is frequently amplified and/or overexpressed across multiple tumor types (including ovarian, endometrial, gastric, and breast cancers), making it an attractive therapeutic target. However, as a non-enzymatic regulatory protein, CCNE1 has been considered difficult to drug with conventional approaches. Our CCNE1 MGD selectively inhibited proliferation of CCNE1-amplified cancer cell lines while sparing non-amplified lines, consistent with the hypothesis that CCNE1 amplification is an indication of oncogene addiction. The antiproliferative phenotype was accompanied by markedly reduced RB phosphorylation and suppression of E2F-driven transcription, supporting an on-target mechanism of action. In addition, we observed strong induction of senescence markers in CCNE1 MGD-treated cells, indicating an exit from the cell cycle. In in vivo studies, orally dosed CCNE1 MGD produced robust tumor growth in...