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CHARLESTON, S.C. — Hydroxychloroquine went from a relatively unknown malaria drug just a few years ago to a highly controversial treatment for COVID-19 during the pandemic. Now, doctors are uncovering surprising ways that this repurposed medication may be the answer for treating cancer.
Although cancer cells can become resistant to hydroxychloroquine, the new findings open the door for more effective combination treatments. Simply put, researchers have discovered how to team this versatile drug with other treatments which cover up any weaknesses hydroxychloroquine may have.
As scientists race to find new weapons in the war on cancer, some are taking a fresh look at old drugs that may have untapped cancer-fighting potential. One such drug is hydroxychloroquine, which has shown promise in attacking cancer cells by disrupting their ability to recycle resources.
Despite hydroxychloroquine’s effectiveness at cutting off this vital lifeline for cancer, clinical trials have been disappointing, with cancer cells often finding ways to overcome the drug’s effects. Now, researchers at the Medical University of South Carolina’s Hollings Cancer Center believe they’ve uncovered the key to this resistance – and it isn’t what they expected.
“We thought the main interaction of hydroxychloroquine with cancer was this process of autophagy, but it appears instead that processes unrelated to autophagy may be the most important for cancer cells to survive this therapy,” explains Joe Delaney, Ph.D., who led the study published in the journal Cell Cycle.
To be clear, autophagy is the cellular recycling process. This surprising finding opens up new possibilities for pairing hydroxychloroquine with other drugs that target these newly identified resistance mechanisms, potentially making the treatment more effective and longer-lasting.
A Two-Pronged Approach to Uncover Resistance
To understand how cancer cells were evading hydroxychloroquine, Delaney and his team took a comprehensive approach, using two different whole-genome screening methods to observe how cells adapted when continuously exposed to the drug.
“Targeting single proteins can be extremely effective to treat cancer,” Delaney notes. “However, the more specific the treatment becomes, the more likely resistance is to occur.”
“By using two completely different methods, we were able to home in on the true biological players in the system,” the researcher continues.
Rather than simply looking at which genes were turned on or off, the researchers were able to see the cascading changes happening across entire cellular pathways. This revealed that cancer cells weren’t modifying their recycling processes at all – instead, they were altering their cell division, metabolism, and export mechanisms to survive the hydroxychloroquine onslaught.
Paving the Way for Combination Treatments
These findings set the stage for developing new combination treatments that could boost the power of hydroxychloroquine. By pairing it with drugs targeting the cell division, metabolism, or export pathways that cancer cells rely on, researchers hope to prevent resistance from developing.
“Our study has identified the potential mechanisms that we will need to target with a second drug to prevent resistance against hydroxychloroquine,” says Delaney.
Additionally, the team believes certain cancer types that already have defects in one of these pathways could be especially vulnerable to hydroxychloroquine treatment. Conversely, patients without these defects may be better suited for other, less resistant therapies.
“We certainly want to understand which patients would see the most benefit to get the best result from these trials,” Delaney concludes.
As the search for effective cancer treatments continues, repurposed drugs like hydroxychloroquine are proving to be a promising avenue of exploration. By unraveling the unexpected ways cancer cells can adapt, researchers are now better equipped to overcome this evasive enemy.
Paper Summary
Methodology
The study examined how cancer cells evolve resistance to hydroxychloroquine (HCQ), a drug often used for its anti-cancer effects. Researchers used a multi-omics approach to get a complete view of how cancer cells change over time with HCQ exposure. They grew two types of resistant cancer cells—ovarian and colorectal—in a lab setting and subjected them to HCQ over multiple treatment cycles.
For genetic analysis, they sequenced cell genomes, performed single-cell RNA sequencing to see individual cell responses, and used CRISPR-Cas9, a gene-editing tool, to pinpoint specific genes involved in HCQ resistance. The various data types—like RNA patterns and genetic changes—were combined to find both known and unexpected pathways that help cancer cells survive HCQ.
Key Results
The study found that cancer cells can resist HCQ in ways that don’t depend on autophagy, the process HCQ usually affects. Instead, the resistant cells changed their genes to upregulate certain pathways, like those involved in energy production and handling cellular stress. They also showed changes in genes that help cells control their chromosomes and divide. This means that the cells found new ways to survive the drug without relying on the expected autophagy pathway.
Study Limitations
The study mainly used two types of cancer cell lines, which means the results might not apply to all cancer types. Also, while the CRISPR screening gave clues about important genes, these findings need further testing to confirm if they are directly responsible for HCQ resistance in real-world cancers. Lastly, using cells grown in a lab can sometimes lead to different results than what happens in the human body.
Discussion & Takeaways
This research reveals that HCQ resistance in cancer cells doesn’t always rely on autophagy. Instead, cells seem to adapt by using other pathways that help them handle stress, grow, and divide, even with HCQ exposure. The findings suggest that to make HCQ more effective, future cancer treatments could target these newly discovered pathways. Overall, the study helps scientists better understand drug resistance in cancer and may guide more effective treatments with repurposed drugs like HCQ.
Funding & Disclosures
The study was funded by several NIH grants, including ones dedicated to cancer research, and also received support from the Hollings Cancer Center and the MUSC Molecular Analytics Core. No potential conflicts of interest were reported by the authors.
