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Cancer Res. 2019 Dec 1;79(23):5971-5985. doi: 10.1158/0008-5472.CAN-19-1961. Epub 2019 Oct 8.

Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition.

Lewis CW1,2,3, Bukhari AB1,2,3, Xiao EJ1,3, Choi WS1,2,3, Smith JD1,2,3, Homola E4, Mackey JR1,5, Campbell SD4, Gamper AM1,2,3, Chan GK6,2,3.

Author information

1
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
2
Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
3
Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada.
4
Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
5
Medical Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
6
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. gkc@ualberta.ca.

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.

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