Abstract
Adavosertib (also known as AZD1775 or MK1775) is a small-molecule inhibitor of the protein kinase Wee1, with single-agent activity in multiple solid tumors, including sarcoma, glioblastoma, and head and neck cancer. Adavosertib also shows promising results in combination with genotoxic agents such as ionizing radiation or chemotherapy. Previous studies have investigated molecular mechanisms of primary resistance to Wee1 inhibition. Here, we investigated mechanisms of acquired resistance to Wee1 inhibition, focusing on the role of the Wee1-related kinase Myt1. Myt1 and Wee1 kinases were both capable of phosphorylating and inhibiting Cdk1/cyclin B, the key enzymatic complex required for mitosis, demonstrating their functional redundancy. Ectopic activation of Cdk1 induced aberrant mitosis and cell death by mitotic catastrophe. Cancer cells with intrinsic adavosertib resistance had higher levels of Myt1 compared with sensitive cells. Furthermore, cancer cells that acquired resistance following short-term adavosertib treatment had higher levels of Myt1 compared with mock-treated cells. Downregulating Myt1 enhanced ectopic Cdk1 activity and restored sensitivity to adavosertib. These data demonstrate that upregulating Myt1 is a mechanism by which cancer cells acquire resistance to adavosertib. SIGNIFICANCE: Myt1 is a candidate predictive biomarker of acquired resistance to the Wee1 kinase inhibitor adavosertib.
Highlights
Adavosertib is a narrow spectrum inhibitor of the protein kinase Wee1 that has singleagent clinical activity in multiple solid tumors, including sarcoma, glioma, head and neck cancer, and ovarian cancer [1, 2].Wee1 activity is crucial for maintaining the S- and G2–M-phase DNA damage checkpoints [3,4,5] and as such adavosertib sensitizes cancer cells to genotoxic treatments including ionizing radiation, gemcitabine, cisplatin, and camptothecin [6,7,8,9,10]
Because the activities of two related kinases Myt1 and Wee1 were found to be redundant in Cdk1 regulation in various organisms/ tissues [19,20,21, 30], we hypothesized that upregulation of Myt1 could underline Wee1 inhibitor resistance
Clinical trials show that adavosertib treatment responses are variable, and some cancers do not respond to adavosertib [1, 16]; the mechanisms of drug resistance are unknown
Summary
Wee activity is crucial for maintaining the S- and G2–M-phase DNA damage checkpoints [3,4,5] and as such adavosertib sensitizes cancer cells to genotoxic treatments including ionizing radiation, gemcitabine, cisplatin, and camptothecin [6,7,8,9,10]. Adavosertib treatment forces S-phase HeLa (cervical cancer cells) and breast cancer cells to directly enter mitosis [10,11,12,13]. This causes premature condensation of underreplicated chromosomes, leading to double-stranded breaks at the centromeres
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