Abstract
BackgroundChk1 forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators. Recent evidence suggests that Chk1 inhibitors may demonstrate significant single agent activity in tumors with specific DNA repair defects, a constitutively activated DNA damage response or oncogene induced replicative stress.MethodsGrowth inhibition induced by the small molecule Chk1 inhibitor V158411 was assessed in a panel of human leukemia and lymphoma cell lines and compared to cancer cell lines derived from solid tumors. The effects on cell cycle and DNA damage response markers were further evaluated.ResultsLeukemia and lymphoma cell lines were identified as particularly sensitive to the Chk1 inhibitor V158411 (mean GI50 0.17 μM) compared to colon (2.8 μM) or lung (6.9 μM) cancer cell lines. Chk1 inhibition by V158411 in the leukemia and lymphoma cell lines induced DNA fragmentation and cell death that was both caspase dependent and independent, and prevented cells undergoing mitosis. An analysis of in vitro pharmacodynamic markers identified a dose dependent decrease in Chk1 and cyclin B1 protein levels and Cdc2 Thr15 phosphorylation along with a concomitant increase in H2AX phosphorylation at Ser139 following V158411 treatment.ConclusionsThese data support the further evaluation of Chk1 inhibitors in hematopoietic cancers as single agents as well as in combination with standard of care cytotoxic drugs.
Highlights
Chk1 forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators
The DNA damage signaling response (DDR) can be activated by a range of endogenous and external insults including therapies currently used for the treatment of cancer such as ionizing radiation and cytotoxic chemotherapeutic agents such as gemcitabine, irinotecan and cisplatin [2,3]
Pharmacological inhibition of Chk1 is cytotoxic in leukemia and lymphoma cell lines Emerging evidence suggests that inhibiting the checkpoint kinase Chk1, in addition to potentiating cytotoxic chemotherapeutic agents, may exhibit single agent activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects
Summary
Chk forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators. The DDR can be activated by a range of endogenous and external insults including therapies currently used for the treatment of cancer such as ionizing radiation and cytotoxic chemotherapeutic agents such as gemcitabine, irinotecan and cisplatin [2,3] Despite their similarity in name, Chk and Chk differ substantially in the structure of their kinase pocket [4,5] and in their cellular function with Chk suggested to be the major component responsible for responses to DNA damage [3,6,7]. Small molecule inhibitors of predominantly the Chk kinase have been readily sought as a mechanism through which the anti-tumor activity of cytotoxic chemotherapeutics may be increased whilst sparing the normal cells [10,11,12] This approach is currently being tested in the clinic with a variety of agents including LY2603618 [13], MK-8776 [14], GDC-0425 and GDC-0575 in combination with a range of standard of care chemotherapy drugs
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