Checkpoint Kinase 1
Chemotherapy and radiation are among the most commonly used cancer treatments. These treatments have achieved significant survival benefits for patients and are likely to remain in use for many years to come. Radiation and chemotherapy work by damaging the DNA of tumour cells resulting in their death. However, because of the high doses required, significant unwanted side effects in addition to treatment resistance are common problems which often lead to a reduced benefit for the patient. Consequently, there has been significant research focused on methods to selectively sensitise tumours to DNA damaging therapies whilst preserving normal cells.
Chk1 belongs to a family of proteins known as kinases and performs a crucial role in the cellular DNA Damage Response (DDR). Although Chk1 is important in all cells, many tumour cells (over 50%) have partially disrupted DNA repair mechanisms leaving them much more reliant on Chk1. As a consequence, inhibition of Chk1 has been shown to selectively sensitise tumours cells to well known DNA damaging agents (e.g. Gemcitabine, Irinotecan & Cytarabine) providing a strong rationale for the development of such drugs in oncology [Clin Cancer Res 16, 2076 (2010)].
Chk1 is phosphorylated by the signalling kinase ATR (ataxia telangiectasia and Rad3 related) following DNA damage
Most cancer cells have impaired G1 checkpoint activation due to a defective p53 tumor suppressor protein
Chk1 inhibition prevents intra S and G2/M checkpoint arrest and drives p53 defective cells into mitotic catastrophe and apoptosis