Researchers at the Virginia Commonwealth University Massey Cancer Center have uncovered a new potential therapeutic target for triple-negative breast cancer (TNBC). The study, published in PNAS Nexus, used CRISPR-Cas9 screening to identify a specific enzyme that, when blocked, could offer new hope for an aggressive form of cancer with limited treatment options.
The trouble with TNBC
Triple negative breast cancer is a particularly aggressive form of the disease that accounts for 10-15% of all breast tumours. It grows and spreads more quickly than other forms and is associated with worse outcomes for patients, accounting for nearly one-third of breast cancer-related deaths.
Targeted therapies have been somewhat of a revolution in cancer treatment, including breast cancers. However, TNBC lacks the hormone receptors, oestrogen receptors or human epidermal growth factor receptor 2 (HER2) that can be targeted in these types of treatment.
“Genomic and clinical evidence suggests that the implementation of targeted therapies in the treatment of TNBC will require an expansion of potential targets,” said Anthony Faber, co-corresponding author of the paper. “Our study may have identified a key and novel target for the development of new therapies.”
Homing in on UBA1
Using CRISPR-CAS9 screening, the team identified the enzyme UBA1 as an ideal therapeutic target. They found that a UBA-inhibiting drug, called TAK-243, managed to block the enzyme’s function and kill cancer cells in patient-derived breast tumours present in mouse models.
Other studies have shown that UBA1 inhibitors can positively impact haematological cancers such as acute myeloid leukaemia. However, this is the first study to outline any impact in breast cancer. What’s more, TAK-243 has recently been tested in early phase clinical trials, meaning there is the potential for this drug to be tested in TNBC patients relatively soon.
In the current study, the team also determined that the c-MYC gene – an important and infamously difficult drug target in TNBC – can be harnessed to cooperate with TAK-243 to initiate a cellular stress response and enhance the drug’s ability to fight TNBC. This supports the notion that TAK-243 may be effective in high-cMYC-expressing TNBC, where c-MYC may serve as a biomarker for response to the drug.
“We found that the majority of TNBC cells in our study were uniformly susceptible to the antitumor effects of TAK-243,” said Jennifer Koblinski, Director of the Cancer Mouse Models Core and member of the Cancer Biology research program at Massey. “In addition to demonstrating this drug’s success at the local site of the primary breast cancer, our findings demonstrate that TAK-243 can also shrink tumours in various organs after the disease has spread.”
A disproportionate disease
TNBC disproportionally affects Black women, who die at a higher rate despite being diagnosed earlier (on average) than white women. It’s therefore vital to find an effective therapy that works in all patients, not just a select few.
“As TNBC is a major disease of disparate outcomes between Black patients and white patients, we were able to harness the power of new breast cancer mouse models from Black TNBC patients that were developed by Dr. Koblinski’s group,” added Faber. “Traditionally, these models have been underrepresented and are important new tools to identify effective therapies for Black patients. The most exciting part of the study was that we found TAK-243 was effective across these models, suggesting TAK-243 or other UBA1 inhibitors could be equally effective in all TNBC patients.”
As for the future, the team hope to explore the use of TAK-243 in TNBC alongside the drug company developing it, and to look for other potential targets in the UBA1 pathway.