Abstract A006: Biomarker analyses of WEE1 inhibition in patients with refractory <i>CCNE1</i> amplified solid tumors

Abstract Background: Preclinical studies have shown that cyclin E overexpression enhances sensitivity to WEE1 inhibition in both in vitro and in vivo models. However, the molecular correlates of response to WEE1 inhibitors in patients with refractory solid tumors harboring CCNE1 amplifications remain poorly characterized. Methods: Patients with CCNE1 amplified solid tumors were enrolled a phase II trial of adavosertib (NCT03253679). Correlative blood and tumor tissues specimens were collected at the baseline and after the treatment initiation. Immunohistochemistry (IHC), RNA sequencing (RNA-seq) and whole exome sequencing (WES) were conducted to correlate with major clinical outcomes. Results: Treatment with adavosertib did not consistently affect downstream protein levels in this heterogenous patient population. The median progression-free survival (PFS) in CCNE1 amplified patients with low CCNE1 protein expression or moderate CCNE1 gene amplificants (&amp;lt;20 copies of CCNE1) was numerically longer than those with high CCNE1 protein expression or super-amplificants (&amp;gt;20 copies), respectively. TP53 aberrations emerged as the most frequent concurrent genomic alterations. Compared with the baseline specimens, on-treatment tissues showed significant increases in the expression of the immunosuppressive genes such as FKBP5, TSC22D3, and PVALB. By pathway-level RNA-seq analyses, non-responders exhibited higher expression of the TGF-beta pathway, while responders showed elevated activity of the PI3K, JAK-STAT and NF-kB pathways. Immune-desert tumor microenvironment (TME) displayed rapid tumor progression in CCNE1 amplified patients treated with adavosertib. Conclusions: Biomarker analyses using IHC, RNA-seq and WES showed WEE1 inhibition induced significantly expression of the immunosuppressive genes. Patients with immune-desert TME at baseline or on treatment responded poorly to WEE1 inhibition, supporting further exploration of WEE1 inhibition in combination with TME-modulated immunotherapy for the treatment of patients with CCNE1 amplified malignancies. Citation Format: Siqing Fu, Camila Braganca Xavier, Khanda Keyomarsi, Yan Wang, Katherine Ferry-Galow, Deborah Wilsker, Francesca Paradiso, Vladimir Kushnarev, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Shuyang Yao, Ying Yuan, Ecaterina Ileana Dumbrava, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Shannon Westin, Funda Meric-Bernstam. Biomarker analyses of WEE1 inhibition in patients with refractory CCNE1 amplified solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A006.