P1/2, N=564, Recruiting, AstraZeneca | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Aug 2027

P1/2, N=29, Recruiting, Incyte Corp.

CCA cells with upregulated CDK2 and its cyclin partners in HG were more sensitive to tagtociclib at a higher dose. Cyclin E and cyclin A also regulated CCA metastasis by controlling epithelial-mesenchymal transition. Targeting CDK2 and its associated cyclins in CCA cells demonstrated therapeutic potential that requires further translational and clinical verification.

P3, N=466, Recruiting, Incyte Corporation | Not yet recruiting --> Recruiting

In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. CRISPR knockout of p21 or p27 in palbociclib-resistant cells eliminated this synergy. Further, RNA sequencing revealed that combination treatment upregulated senescence and interferon pathways, providing mechanistic insight into the observed therapeutic synergy.

P1/2, N=564, Recruiting, AstraZeneca | N=348 --> 564

P1, N=9, Completed, Incyte Corporation | Recruiting --> Completed

P1/2, N=205, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=9, Completed, Pfizer

P1/2, N=205, Not yet recruiting, Novartis Pharmaceuticals

The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53% and 33% respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.

WNTinib's efficacy was assessed in three animal models (n = 48): (a) patient-derived xenograft (PDX) HB tumors (n = 5 CTNNB1-mutant, n = 1 CTNNB1 wild-type) implanted in NSG mice; (b) PDX-derived TT001- and (c) HepG2-HB cells subcutaneously implanted in Fox1nu mice; and in two patient-derived organoids from CTNNB1-mutant HBs. In HB organoids, WNTinib demonstrated greater efficacy than standard-of-care cisplatin (P = 0.009, org-1), and its antitumor effect was further enhanced when combined with chemotherapy (P = 0.01, org-1; P = 0.007, org-22). WNTinib delays tumor progression and increases survival in CTNNB1-mutated HB models, providing rationale to explore its use in human HB.