The future of fighting cancer isn't always about creating new drugs—sometimes, it's about discovering hidden superpowers in old ones.
Imagine a veteran drug, used for decades to treat leukemia, suddenly revealing a remarkable new talent: the ability to eliminate tumors that have outsmarted the latest targeted cancer therapies. This isn't science fiction—it's the exciting story of 6-thioguanine (6TG), a chemotherapy agent that scientists have discovered can selectively destroy certain treatment-resistant cancers.
6TG appears to overcome several different resistance mechanisms that currently leave clinicians with few options for treating aggressive BRCA1- and BRCA2-defective cancers.
The discovery offers new hope for patients with aggressive BRCA1- and BRCA2-defective cancers that have developed resistance to modern treatments like PARP inhibitors. What makes this finding particularly compelling is that 6TG appears to overcome several different resistance mechanisms that currently leave clinicians with few options.
To understand why this discovery matters, we need to look at how our cells protect themselves against cancer—and how cancers exploit these systems.
The first responder that rushes to fix single-strand breaks in DNA3
The specialized repair team that handles the more complex double-strand breaks through a process called homologous recombination3
These systems are so crucial that when they fail, the consequences can be severe. People born with mutations in their BRCA genes have significantly higher risks of developing breast, ovarian, prostate, and pancreatic cancers because their cells struggle to repair DNA damage properly1 .
The relationship between PARP and BRCA opened one of the most promising avenues in modern cancer treatment: synthetic lethality. This clever approach exploits the fact that while cancer cells can survive with just one of these repair systems broken, losing both is fatal.
"PARP inhibitors were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers"3 .
For patients with BRCA mutations, PARP inhibitors like olaparib have been groundbreaking. They cripple the backup DNA repair system, creating a situation where cancer cells can't fix either single or double-strand breaks, leading to their destruction while sparing healthy cells.
BRCA Mutation
PARP Inhibitor
Cancer Cell Death
Despite initial success, a major challenge has emerged: cancer cells often develop resistance to PARP inhibitors. Through various clever mechanisms, tumors find ways to survive what should be lethal attacks4 :
Some cancer cells develop secondary mutations that restore the function of previously defective BRCA genes
Tumors increase production of P-glycoprotein pumps that actively eject PARP inhibitors from cancer cells
Cancers sometimes activate backup DNA repair systems
This resistance problem has created an urgent need for new treatment strategies that can overcome these evasion tactics.
In search of solutions, scientists conducted a systematic screen of compounds that might selectively kill BRCA2-defective cells. Among the candidates, one unexpected drug stood out: 6-thioguanine (6TG), a purine analog used since the 1960s to treat leukemia1 5 .
Researchers discovered that 6TG induces multiple types of DNA damage that require functional homologous recombination for repair. While healthy cells can handle this damage, BRCA2-defective cancer cells cannot1 .
To validate these findings, researchers designed comprehensive experiments comparing 6TG's effectiveness against various cancer cell lines and living tumor models1 .
Even when BRCA2 function was partially restored through genetic reversion—a common resistance mechanism—the cancer cells remained sensitive to 6TG. This suggested that 6TG creates multiple types of DNA lesions that still require full homologous recombination capacity for repair1 .
| Cell Type | BRCA Status | PARP Inhibitor Response | 6TG Response | Key Finding |
|---|---|---|---|---|
| HCT116 BRCA2-deficient | BRCA2 defective | Sensitive | Highly sensitive | Selective killing of defective cells |
| Capan-1 PARPi resistant | BRCA2 reversion | Resistant | Sensitive | Overcomes genetic resistance |
| Spontaneous BRCA1 mammary tumors | BRCA1 defective | Resistant (P-glycoprotein) | Sensitive | Overcomes pump-based resistance |
| Castration-resistant prostate cancer | BRCA2 deficient | Sensitive | Highly sensitive | Effective in multiple cancer types5 |
The secret to 6TG's success against resistant cancers lies in the multiple types of DNA damage it creates1 2 :
That require homologous recombination for repair
That still depend on BRCA2 function
That overwhelm partially restored repair systems
This multi-mechanism attack makes it difficult for cancer cells to develop resistance through a single adaptation. Even when homologous recombination is partially restored in resistant cells, it's insufficient to handle all the different types of damage caused by 6TG.
| Drug/Treatment | Primary DNA Damage | Key Repair Pathway | Resistance Mechanisms |
|---|---|---|---|
| PARP Inhibitors | Single-strand breaks progressing to double-strand breaks | Homologous recombination | BRCA reversion, P-glycoprotein pumps |
| Platinum Drugs | DNA cross-links | Homologous recombination | BRCA reversion, enhanced tolerance |
| 6-Thioguanine | Multiple lesions including DSBs and MMR-independent damage | Fully functional homologous recombination | Limited resistance observed |
Controlled silencing of BRCA2 expression allows reversible creation of BRCA2-defective cells for comparison.
Collections of known chemical compounds used as source for drug screening and discovery.
Separation of large DNA fragments for detection and quantification of DNA double-strand breaks.
Human tumors grown in mice for testing drug effectiveness in living organisms.
Subsequent research has revealed that 6TG's potential extends beyond BRCA-defective cancers. Studies in castration-resistant prostate cancer—an aggressive form that often develops resistance to standard therapies—show that 6TG effectively kills cancer cells, with response depending on BRCA2 status5 .
As one study noted, 6TG "may be effective in the treatment of advanced tumours that have developed resistance to PARP inhibitors or platinum-based chemotherapy"1 .
The story of 6-thioguanine reminds us that medical breakthroughs don't always come from entirely new discoveries—sometimes they're hiding in plain sight. This sixty-year-old drug has revealed a surprising new capability that could offer hope to patients with treatment-resistant cancers.
While more research is needed to optimize dosing and determine which patients will benefit most, 6TG represents a promising strategy against some of the most challenging cancers we face today. It demonstrates that even as cancers evolve resistance to our newest targeted therapies, scientific ingenuity can find ways to fight back—sometimes by taking a fresh look at old tools.
As research continues, drug repurposing initiatives may reveal more hidden gems in our existing medical arsenal, potentially offering new hope to patients who have exhausted conventional treatment options.
The rediscovery of 6-thioguanine represents the exciting potential of looking back through our existing medical toolkit to find future cancer solutions.