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.

Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy (CCNE1 amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models.

P1, N=50, Terminated, Blueprint Medicines Corporation | Phase classification: P1/2 --> P1 | N=366 --> 50 | Trial completion date: Sep 2026 --> Jul 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2025 --> Jul 2025; This trial was terminated prior to the initiation of Phase 2 for reasons not due to safety concerns.

FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.

Our findings indicate that the combination of AZD5438 and PD0325901 holds therapeutic potential for the treatment of HPV (-) HNSCC, particularly in tumors with a high mutational burden. By targeting complementary pathways, this combination may improve treatment outcomes in this aggressive cancer subtype.

P1, N=51, Recruiting, Incyte Corporation | Completed --> Recruiting | N=15 --> 51 | Trial completion date: May 2025 --> Mar 2026 | Trial primary completion date: May 2025 --> Feb 2026

P1, N=258, Recruiting, BeiGene | Trial completion date: Feb 2028 --> Jul 2028

P1, N=9, Recruiting, Incyte Corporation | Not yet recruiting --> Recruiting

P1, N=9, Not yet recruiting, Incyte Corporation

P3, N=466, Not yet recruiting, Incyte Corporation

This study designed and synthesized two series (A and B) of 28 unreported compounds based on rational structural modification of the lead compound AZD5438...Mechanistic studies demonstrated that B11 induces apoptosis in HCT116 cells by elevating intracellular ROS levels through suppression of anti-apoptotic protein expression and activating the caspase-3 pathway. In conclusion, compound B11 may serve as a novel selective CDK9 inhibitor worthy of further development for colorectal cancer treatment.