A common genetic mutation that helps some kidney cancers survive may also expose an unexpected weakness, one that MUSC Hollings Cancer Center researchers hope to transform into a new treatment strategy.
In a new study published in Cancer Research , Aguirre de Cubas, Ph.D ., and colleagues discovered that kidney cancer cells lacking the tumor suppressor gene SETD2 become highly dependent on a protein called BCL-xL for survival. By targeting that dependency, the researchers were able to selectively eliminate SETD2-deficient cancer cells in laboratory models while largely sparing cancer cells with intact SETD2. The findings identify a potential new therapeutic strategy for patients with a particularly aggressive subset of kidney cancers.
That discovery laid the foundation for a newly awarded five-year, multi-million-dollar National Cancer Institute (NCI) grant . The grant will support efforts to understand why SETD2-deficient tumors become dependent on BCL-xL and whether that vulnerability can be leveraged to develop more effective treatments.
"These projects are two parts of the same scientific journey," de Cubas said of the study and grant. "The study revealed a previously unrecognized vulnerability in SETD2-mutant kidney cancers. The grant now gives us the opportunity to understand the biology behind that vulnerability and whether it can be translated into a new therapeutic strategy for patients."
SETD2 is one of the most frequently altered tumor suppressor genes in human cancer, with alterations occurring in approximately 5% of all solid malignancies. It is particularly common in clear cell renal cell carcinoma, which accounts for almost three-quarters of all kidney cancers and is difficult to treat once it spreads beyond the kidney.
Researchers estimate that roughly 20% to 25% of tumors lose the gene entirely, and patients whose tumors carry SETD2 alterations often experience more aggressive disease and poorer outcomes. Despite its prevalence and clinical importance, researchers have struggled to understand why losing SETD2 confers a selective advantage to kidney tumors.
"The central question was why tumors experience loss of SETD2 in the first place,” de Cubas said. “SETD2 is one of the most frequently mutated genes in kidney cancer, yet we don’t fully understand what advantages its loss provides to tumor cells. Understanding that biology could reveal vulnerabilities that can be exploited therapeutically, which is important for patients with limited treatment options."
To answer that question, his team searched for what cancer biologists call "synthetic lethal vulnerabilities,” or hidden weaknesses that emerge when a cell acquires a cancer-promoting mutation. In these cases, the mutation creates an unexpected dependence on another gene or protein for survival. By targeting that dependency, researchers can selectively eliminate cancer cells while leaving normal tissues largely unharmed, creating opportunities to develop more precise and effective therapies or improve existing ones.
Their search revealed a dependency on BCL-xL, a protein that acts as a cellular bodyguard by preventing programmed cell death. While most cells can survive without relying heavily on BCL-XL, kidney cancer cells lacking SETD2 had become remarkably dependent on it.
When the researchers blocked BCL-xL, the results were striking. SETD2-deficient cancer cells died rapidly, whereas kidney cancer cells with intact SETD2 remained largely unaffected.
"It was an unexpected finding," de Cubas said. "What we uncovered was essentially an Achilles’ heel. By losing SETD2, these tumors gain certain advantages that help them grow, but they also become highly dependent on BCL-xL for survival. That dependency creates a therapeutic opportunity."
Investigating that vulnerability led researchers to the mitochondria.
Often described as the cells’ powerhouses, mitochondria contain their own DNA separate from the genetic material housed in the cell nucleus. Under normal circumstances, that DNA remains safely confined within the mitochondria. But the researchers found that cells lacking SETD2 experienced mitochondrial stress that caused small amounts of DNA to leak into the cell's interior.
That leakage raised cellular alarm bells. Because, according to de Cubas, "DNA is not supposed to be floating around in the cytoplasm. When the cells detect DNA where it shouldn't be, they interpret it as a danger signal, often resembling a viral infection.”
The leaked mitochondrial DNA activated a molecular pathway known as cGAS-STING, which serves as part of the body’s innate immune defense system that evolved to detect viral pathogens. The result was a persistent inflammatory state that fundamentally changed the biology of SETD2-deficient cancer cells.
"When we treated the cells with BCL-xL inhibitors, we amplified an inflammatory program that was already smoldering," de Cubas said. "The cells essentially behaved as though they were responding to a viral infection, pushing them toward a point they could no longer tolerate."
The effect was twofold. BCL-xL inhibition drove cancer cells toward self-destruction while simultaneously increasing inflammatory signals that made them more visible to the immune system.
"What makes this particularly exciting is that the biology appears to be interconnected," de Cubas said. "The same mitochondrial stress that helps create the vulnerability may also contribute to immune activation, potentially giving us multiple ways to exploit the weakness therapeutically."
The findings also help to solve one of kidney cancer's longstanding mysteries.
Unlike cancers such as melanoma or lung cancer, kidney tumors often respond surprisingly well to immunotherapy despite carrying relatively few mutations that would be expected to make them visible to the immune system. During the study, de Cubas and colleagues found evidence that mitochondrial DNA leakage may contribute to the inflammatory signal that makes kidney tumors immunologically active.
"We think mitochondrial DNA may have a much more central role in kidney cancer immunogenicity than previously appreciated,” de Cubas said.
The discovery also challenges prevailing assumptions about the source of inflammatory signaling in SETD2-deficient tumors. Because the loss of SETD2 is known to cause chromosomal instability and the formation of micronuclei – small fragments of misplaced nuclear DNA that can activate immune pathways – many researchers had assumed that micronuclei were the primary trigger of inflammation in these cancers.
Instead, de Cubas' team found that mitochondrial DNA leakage was a much stronger driver of cGAS-STING activation.
"The field has largely focused on micronuclei as the source of inflammatory signaling in SETD2-deficient cells," de Cubas said. "What we found is that mitochondrial DNA leakage appears to be the dominant signal. The micronuclei were there, but they may have been masking a much more important mechanism."
The findings may also help to resolve broader questions about what drives immune activation in kidney tumors. The new work points to mitochondrial DNA leakage as a central initiator of inflammatory pathway responses.
The newly awarded NCI grant will build directly on these findings by pursuing two fundamental questions. de Cubas and his team will investigate what causes mitochondrial DNA leakage in SETD2-deficient tumors and whether that process can be exploited to make tumors more susceptible to treatment.
The researchers will also investigate whether combining BCL-xL inhibition with immune checkpoint blockade therapies can produce a more potent anti-tumor response. Because BCL-xL inhibition appears to amplify antiviral-like inflammatory signaling in SETD2-deficient tumors, the combination could make these cancers more responsive to immunotherapy.
The work also highlights the collaborative nature of research at Hollings. de Cubas credited co-authors Tim Barnoud, Ph.D ., Jezabel Rodriguez Blanco, Ph.D. , and Thai Ho, M.D., Ph.D. , with helping to shape the project and refine its scientific direction. The study also relied heavily on the services and capabilities of Hollings’ Flow Cytometry and Cell Sorting and Cell and Molecular Imaging shared resources.
Although the findings remain preclinical, de Cubas believes they provide a strong foundation for future translational studies. The new award will allow his laboratory to expand its research program and recruit additional post-doctoral fellows and research staff to pursue these questions.
"If we can overcome some of the challenges associated with targeting BCL-xL, the effect we see in SETD2-mutant tumors is remarkably strong," he said. "We now have a clear path forward for understanding the underlying tumor biology and, most importantly, whether we can use that knowledge to develop better therapies for patients."
Cancer Research
Experimental study
Cells
SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-xL in Clear Cell Renal Cell Carcinoma
2-Jun-2026
T.H. Ho reports personal fees from Eisai, Merck, AstraZeneca, Cardinal Health, and Exelixis outside the submitted work. No disclosures were reported by the other authors.