Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia.
Kamal ChamounGautam BorthakurPublished in: Expert opinion on investigational drugs (2018)
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.
Keyphrases
- acute myeloid leukemia
- cell cycle
- dna damage
- cell cycle arrest
- allogeneic hematopoietic stem cell transplantation
- chemotherapy induced
- early stage
- clinical trial
- cell therapy
- cell death
- single cell
- oxidative stress
- cell proliferation
- induced apoptosis
- dna repair
- locally advanced
- stem cells
- lymph node
- randomized controlled trial
- phase ii
- systematic review
- cell free
- circulating tumor
- rectal cancer
- phase iii
- endoplasmic reticulum stress
- young adults
- smoking cessation
- human health
- squamous cell
- replacement therapy