ORCID Profile
0000-0002-5983-3571
Current Organisation
University of Sydney
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Publisher: Wiley
Date: 14-06-2019
Abstract: Drugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR–CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress‐inducing drugs. Here, we investigated the effect of low‐level replication stress induced by low concentrations ( 0.2 m m ) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S‐phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in 70% of melanoma and non‐small‐cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo . Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR–CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo . These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.
Publisher: MDPI AG
Date: 06-09-2019
Abstract: The poor selectivity of standard cytotoxic chemotherapy regimens causes severe side-effects in patients and reduces the quality of life during treatment. Targeting cancer-specific vulnerabilities can improve response rates, increase overall survival and limit toxic side effects in patients. Oncogene-induced replication stress serves as a tumour specific vulnerability and rationale for the clinical development of inhibitors targeting the DNA damage response (DDR) kinases (CHK1, ATR, ATM and WEE1). CHK1 inhibitors (CHK1i) have served as the pilot compounds in this class and their efficacy in clinical trials as single agents has been disappointing. Initial attempts to combine CHK1i with chemotherapies agents that enhance replication stress (such as gemcitabine) were reported to be excessively toxic. More recently, it has emerged that combining CHK1i with subclinical doses of replication stress inducers is more effective, better tolerated and more compatible with immunotherapies. Here we focus on the lessons learned during the clinical development of CHK1i with the goal of improving the design of future clinical trials utilizing DDR inhibitors to target replication stress in cancer.
Location: No location found
No related grants have been discovered for Deborah Nazareth.