Abstract Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that play a crucial role in regulating cell cycle progression. Over the past decade, CDK4/6 inhibitors such as ribociclib have significantly improved outcomes in patients with HR+/HER2− breast cancer and have transformed the treatment landscape. Despite their clinical success, multiple mechanisms of resistance to endocrine therapy (ET) plus CDK4/6 inhibitor combinations have been proposed. Several mechanisms, including increased expression of cyclin E, converge on CDK2 activation, enabling bypass of CDK4/6mediated cellcycle inhibition. These mechanisms have driven the development of several CDK2 inhibitors currently in clinical development. ECI830 is an orally bioavailable and potent ATP-competitive inhibitor of CDK2 with high selectivity across other CDKs coupled with favorable drug-like properties. In HR+/HER2− breast cancer cell lines, the combination of ECI830 and ribociclib reveals an enhanced and synergistic activity with deeper pathway modulation (phosphorylated retinoblastoma protein 1 pRB1, E2F target gene expression and G1 cell cycle arrest) and stronger growth inhibition than either agent alone. Similarly, in vivo treatment with ECI830 in combination with ribociclib (and/or ET) results in profound pRB modulation and antitumor activity in HR+/HER2− breast cancer cell line-derived xenograft (CDx; MCF7) and patient-derived xenograft (PDx) models from pre-treated patients. In addition, single-agent tumor growth inhibition has been observed in CCNE1-amplified CDx models. ECI830 induces potent antiproliferative activity correlating with suppression of pRB1, demonstrating on-target and on-pathway activity. In summary, ECI830 is a potent and highly selective CDK2 inhibitor with promising preclinical activity both as a monotherapy (in CCNE1-amplified cancers) and in combination with ribociclib and/or ET (in HR+/HER2− breast cancer). ECI830 is currently being investigated in phase 1 clinical trials as a single agent and in combination with ribociclib and fulvestrant in patients with advanced HR+/HER2- breast cancer and other advanced solid tumors harboring CCNE1 amplification. Citation Format: Samuel Ho, Ophelia Maertens, Bradley French, Eric Fang, Imad Hanna, Ying Huang, Sajan Joseph, Fallon Lin, Neil Umbreit, Anna Uvarova, Vivek Rauniyar. ECI830, a potent and highly selective CDK2 inhibitor, for the treatment of HR+/HER2− breast cancer and CCNE1-amplified tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr ND06.
Ho et al. (Fri,) studied this question.