Dr Burtness on the Exploration of VIC1911 and Adavosertib in HNSCC and Lung Cancer

Barbara Burtness, MD, professor of medicine, Medical Oncology, chief translational research officer, chief, Head and Neck Cancers/Sarcoma, co-leader, Developmental Therapeutics, associate cancer center director for translational research, Yale Cancer Center, discusses preclinical data on the combination of VIC1911 and adavosertib in head and neck squamous cell carcinoma (HNSCC) and lung cancer.

Previous research has shown that Aurora kinase A (AURKA) is overexpressed in cells that have a mutational loss of TP53 function, making AURKA a promising therapeutic target, Burtness begins. In a preclinical study presented at the 2023 AACR Annual Meeting, the AURKA inhibitor, VIC1911 was combined with the WEE1 inhibitor adavosertib. Altough VIC1911 does not have some of the toxicities of prior AURKA inhibitors, this treatment is not cytotoxic because it leads to the cell going into cell cycle arrest, Burtness says.

However, combining VIC1911 with a WEE1 inhibitor could take these cells out of arrest and shift them into mitosis, and since they will not be able to complete a normal mitosis cycle, they will enter apoptosis and mitotic catastrophe, Burtness explains.

Data showed that in cell line–derived xenografts and patient-derived xenografts, VIC1911 decreased DNA replication fork progression, phosphorylation of replication protein A was upregulated, and DNA damage was upregulated, Burtness says. The addition of Adavosertib amplified those effects, she says, adding that almost no normal mitotic figures that can form with this combination.

These findings could lead to a first-in-human phase 1 trial to evaluate if this combination could be active in patients with HNSCC or lung cancer who harbor p53 mutations, Burtness concludes.