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.
Highlights
Many conventional cytotoxic chemotherapies suppress the proliferation of cancer cells by blocking DNA synthesis via inhibiting nucleotide production or generating inter-strand DNA crosslinks
While many chemotherapies promote replication stress, our model suggests that those promoting high level replication stress by imposing an S phase arrest are likely to have high levels of normal tissue toxicity and disable the immune responses
Exploiting replication stress that is commonly elevated in cancers by inhibiting key regulators of the stress response mechanism is a promising strategy for tumour selective treatment
Summary
Many conventional cytotoxic chemotherapies suppress the proliferation of cancer cells by blocking DNA synthesis via inhibiting nucleotide production Many targeted cancer treatments have emerged that focus on tumour specific drivers (e.g., BRAF inhibitors to combat mutant BRAF-dependent melanomas and antibody-based therapies to address over-expression or aberrant EGFR signaling). The advantage of these targeted approaches is the relative ease of identification of the patients likely to benefit, i.e., patients with the mutation or amplification, while a major shortcoming is the reliance on the presence of a single defect which allows solid cancers in particular to rapidly develop resistance to these targeted agents [1]. We will discuss approaches to improve targeting of tumours with elevated replication stress while minimizing normal tissue toxicity, of the innate and adaptive immune system
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