Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia

ABSTRACT

Introduction: Acute myeloid leukemia (AML) is the most common myeloid malignancy in adults. Despite recent discoveries of targeted therapies, the frontline therapy consisting of chemotherapy remains unchanged for the past four decades. Like other cancers, AML is characterized by deranged DNA damage repair (DDR) pathway. Although impaired DDR may contribute to the pathogenesis of AML it also allows leukemia cells with damaged DNA to attempt repair resulting in resistance. CHK1 inhibitors reverse the cell cycle arrest, disallowing the cell to repair the chemotherapy-induced DNA damage, driving the cell to enter into mitotic catastrophe.

Areas covered: This paper reviews the preclinical and clinical development of CHK1 inhibitors and we discussed their promising role as a potential addition to the therapeutic arsenal of AML.

Expert opinion: Targeting the cell cycle checkpoints is an intriguing approach to treat cancer in general and AML in particular. CHK1 inhibitors in combination with chemotherapy have the potential of improving outcome in high-risk AML characterized by DDR activation.

KEYWORDS:

• CHK1 inhibitor
• DNA damage repair pathway
• cell cycle inhibitors
• acute myeloid leukemia

Article highlights

• DNA damage response (DDR) causes cell cycle arrest in leukemia cells with damaged DNA or stalled replication forks to attempt DNA repair rather than undergo apoptosis, contributing to chemotherapy resistance.

• High cell cycle checkpoint kinase 1 (CHK1) expression is associated with poor outcome in acute myeloid leukemia (AML).

• Inhibiting CHK1 reverses the cell cycle arrest before the completion of DNA repair, driving the cell to enter into mitotic catastrophe.

• Early clinical trials combining CHK1 inhibitors with cytarabine in relapsed/refractory AML failed to show clinical benefit.

• Prexasertib is currently being tested in combination with cytarabine and fludarabine in a phase 1 clinical trial for patients with relapsed/refractory AML.

• CHK1 inhibitors can potentially be combined with chemotherapeutic agents in AML or with ATR, WEE1 kinase or BCL-2 inhibitors.

Declaration of interest

G. Borthakur is a primary investigator on a Phase I clinical trial on LY2606368. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

A reviewer on this paper declares running a company developing novel FLT3 inhibitors for acute myeloid leukemia, but have no other relevant financial relationships to disclosure.

Additional information

Funding

This paper was not funded.