RE: Synthetic lethal combination of SAR737 and WEE1 inhibition for treatment of castration-resistant prostate cancer25 Jan 2024 15:42
In our study, SRA737 exhibited significant single-agent activity in suppressing CRPC tumor growth and metastasis in a TRAMP mouse model. It was also well-tolerated in the 4-week treatment study, with no consequential body weight loss or gross toxicity. These preclinical data support the potential of SRA737 as a treatment for CRPC. CHK1 inhibitors have been investigated in many clinical and preclinical studies. Despite their promising therapeutic potential [12], the low selectivity and toxicity often associated with CHK1 inhibitors have been the primary roadblocks for translating these agents to the clinic [32]. SRA737 is a newer generation and highly selective orally available CHK1 inhibitor that exhibits >1000-fold selectivity against CHK2 and CDK1 (IC50: 0.32 nM for CHK1 and 697 nM for CHK2) [33, 34]. SRA737 demonstrated favorable safety and efficacy when combined with gemcitabine in preclinical non-small cell lung cancer (NSCLC) and MYC-driven B-cell lymphoma mouse models [33]. Importantly, recent reports from the only two clinical trials on SRA737 in advanced cancers (NCT02797964 and NCT02797977) demonstrated unique features of this drug, including lower myelotoxicity and higher but manageable GI toxicities that are distinct from other CHK1 inhibitors examined in the clinic [18, 35]. Particularly, despite no complete or partial RECIST responses were observed in one trial that included 13 mCRPC patients, 8/13 (61.5%) mCRPC patients showed stable disease after four cycles of therapy, demonstrating its potential for use in combination therapy.
In summary, our study identified WEE1 and CHK1 kinases, two critical DDR and G2/M checkpoint regulators, as potential novel therapeutic targets for CRPC. We further demonstrated the efficacy and tolerability of the WEE1 inhibitor AZD1775 and CHK1 inhibitor SRA737 as single agents and in combination for CRPC/NEPC treatment in a transgenic mouse model of advanced prostate cancer. Our findings provide solid preclinical support for the further evaluation of these agents for the treatment of lethal prostate cancer.
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