Scientists have found that the antimalarial drug quinacrine can exploit a vulnerability in cancers that become reliant on the NDRG1 protein to sustain their DNA damage response. Published in Science Signaling, their study not only identifies NDRG1 as a promising therapeutic target, but also demonstrates a new strategy for discovering similar vulnerabilities across multiple types of cancer.
“Our findings suggest that NDRG1 expression could serve as a biomarker to help identify patients most likely to benefit from therapies targeting this pathway,” said Garik V. Mkrtchyan, PhD, assistant professor at the University of Copenhagen and lead author of the study. “We further showed that high NDRG1 expression predicts poor survival across multiple cancers, and that inhibiting NDRG1 creates vulnerabilities, highlighting new opportunities for precision oncology.”
Mkrtchyan and colleagues set out to identify new targets for cancer therapeutics by leveraging the concept of synthetic lethality—a phenomenon where cancer cells can survive the loss of one of two genes but die when both are inhibited. This approach has already proven successful in ovarian, breast, and prostate cancers with BRCA mutations, which are particularly vulnerable to PARP inhibitor drugs.
“In oncology, this concept is particularly promising because cancer cells often harbor mutations in specific DNA damage response pathways, making them highly dependent on the remaining repair mechanisms for survival,” said Mkrtchyan. “Targeting these dependencies enables selective elimination of cancer cells while sparing healthy tissue.”
Using transcriptomics data, the researchers identified quinacrine as a promising candidate for disrupting the DNA damage response by targeting the stress-response protein NDRG1. Quinacrine has been used as an antimalarial drug for nearly a century, later gaining approval as a treatment for lupus. In recent years, the compound has attracted growing interest as a potential cancer treatment.
Screening through hundreds of cancer cell lines revealed that blood cancers, which generally showed high NDRG1 expression, were the most sensitive to the drug. Colorectal cancer cells were also sensitive to quinacrine, especially those with mutations in the MLH1 and PARP3 genes. The team later confirmed these findings in patient datasets, where high NDRG1 expression together with loss of either of these genes correlated with improved survival rates.
“While quinacrine has previously been reported to possess anticancer activity, our study uncovers upstream mechanisms of its action on DNA damage response,” said Mkrtchyan. “By applying an automated robotics screen across more than 130 cancer cell lines, we identified novel synthetic lethal interactions involving NDRG1, providing a framework for discovering new therapeutic vulnerabilities across multiple cancer types.”
Despite its potential as a cancer therapy, quinacrine can potentially cause unwanted side effects. The researchers therefore plan to explore alternative drug candidates that can inhibit NDRG1 with more potency while reducing toxicity.
“The next steps will be to develop small molecules that inhibit NDRG1 with greater potency and specificity than quinacrine, thereby minimizing potential off-target effects,” said Mkrtchyan. “From a translational perspective, we aim to validate the identified synthetic lethal interactions in preclinical tumor models and investigate whether targeting the NDRG1 axis can overcome treatment resistance across a broader range of cancers.”
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