Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy

ABSTRACT

Introduction: Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most.

Areas covered: This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies.

Expert opinion: A majority of the current clinical trials focus on AZD1775 combined with chemotherapy or radiation. Treatment with AZD1775 was tolerated, and antitumor activity has been observed, especially in patients with advanced malignancies harboring G1 checkpoint aberrations and/or DNA damage repair defects. Thus, identification of the molecular subtypes that benefit most from the treatment with AZD1775 alone or in combination may provide a novel strategy for cancer therapy. Research is needed for devising regimens to explore AZD1775 in combination with biologically targeted agents and/or immunotherapy (low dose vs. high dose, intermittent vs. continuous, sequential vs. concurrent, etc.) for identifying potential biomarkers predictive of response and survival.

KEYWORDS:

• AZD1775
• Wee1 kinase
• cell cycle checkpoints
• DNA damage repair
• targeted therapy
• immunotherapy
• and early drug development

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Article highlights

• Cell proliferation is tightly controlled by cell cycling checkpoints and DNA damage repair (DDR) pathways.

• Cancer is characterized by aberrations in the cell cycle, defects in the DDR pathways, and tumor escape from immune surveillance.

• Because genetic aberrations occur frequently in G1 checkpoint, cancer cells rely on the S and G2-M checkpoints to maintain genomic integrity.

• Wee1 kinase is a key regulator of the G2-M checkpoint, allowing cells to have sufficient time for DDR.

• AZD1775, currently the only Wee1 inhibitor in clinical development, is a strong inhibitor of Wee1–2 and can abrogate the G2-M checkpoint, resulting in mitotic catastrophe and apoptosis.

• Further exploration of AZD1775 for cancer therapy either alone or as a combination with sequential chemotherapy, concurrent/sequential biologically targeted agents, or immunotherapy in selected population is warranted.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

One of the reviewers has received research funding from AZ and served as an advisor. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.