Doug Cole, MD
Managing Partner, Flagship Pioneering
Researchers at the Dana-Farber Cancer Institute have uncovered how one of the most frequently mutated protein assemblies in cancer is built and functions inside human cells. This series of breakthroughs, led by Cigall Kadoch, PhD, Professor of Pediatric Oncology and Meredith and Billy Starr Investigator at Dana-Farber, and Investigator of the Howard Hughes Medical Institute, provides insights that are opening new avenues for therapies against a top target implicated in more than 20% of all human cancers. Various technologies related to this discovery have been licensed to Foghorn Therapeutics to carry forward.
Understanding Chromatin Remodeling
At the heart of this advance is a molecular “machine” called the mammalian SWI/SNF (mSWI/SNF or BAF) complex, which plays a vital role in chromatin remodeling—the process of rearranging how DNA is packaged inside the cell’s nucleus. Normally, DNA is tightly wound around proteins called histones, forming chromatin that can hide certain genes from being accessed and read. The multi-component mSWI/SNF protein complex works to loosen or reposition this packaging along the genome, switching genes on or off at precisely the right times. When parts of the complex are damaged or mutated, this control can be lost, allowing cells to function abnormally and grow unchecked—key hallmarks of cancer.
A Hidden Driver of Cancer
Kadoch explains that the path toward understanding this process began in full force more than a decade ago, inspired by a wave of high-throughput sequencing studies that identified the genetic culprits behind many cancers. Among the most frequently mutated entities were the genes encoding mSWI/SNF complexes. At around the same time, large-scale studies also enabled by sequencing such as the Cancer Dependency Map (DepMap) were identifying which genes cancer cells rely on most to survive. Again, mSWI/SNF complexes stood out as critical vulnerabilities; this meant that disrupting the complex could potentially collapse a cancer cell’s ability to function, nearly immediately nominating it as a top-ranked target.
Yet, very little was known about these complexes in human cells. Specifically, the field lacked knowledge as to the full componentry (i.e. protein subunit members) of these complexes, how the proteins in the complex fit together, in what combinations, engaging what other nuclear interacting partners, and with what specialized functions. At the time, most existing research had focused on isolated components or studies in simplified systems, such as yeast or flies. There was no clear understanding of how the full complex assembled and which subunits contributed which activities, leaving major challenges in interpreting the amassing human cancer genetics and informing the cancer-promoting defects caused by mutations seen in human tumors.
“Given the unexpectedly outsized role in cancer, there was pressure to immediately start using very conventional approaches to try to study and drug the complex, but we felt strongly that, though arduous, getting answers to how this machine fits together was the first key needed to unlock its full therapeutic potential,” Kadoch stresses.
Mapping the Machine
Kadoch’s lab developed novel biochemical methods to study entire complex assemblies—in both normal and cancer contexts—in their native forms. This meant capturing full protein complexes directly from human cells and using systematic experiments perturbing each subunit one by one to define how the components fit together and act on chromatin.
“Without this, it was like trying to build a complicated piece of machinery without the instruction manual,” Kadoch says. “We had to create that manual from scratch.”
Her team’s work in this area ultimately led to a landmark paper published in Cell in 2018, which described a new strategy for isolating and characterizing the complex. The team’s approach allowed them to study the full assembly at scale, enabling insights that had previously been out of reach.
This foundational work also enabled a second major study published in Cell in 2020, which revealed the 3D structure of the complex and further clarified its role in regulating chromatin architecture—the way DNA is folded and organized in the cell—in both normal and cancer states. The group has since uncovered its functions and unmasked new vulnerabilities in a range of human cancer types, including most recently in a publication in Science explaining how mSWI/SNF complexes are essentially ‘hijacked’ to activate pro-cancer genes in certain cancers.
The ability to study these complexes in their native forms and to integrate a suite of powerful methods to probe their functions has changed the game for how we think about targeting cancer.
Cigall Kadoch, PhD
What It Means for Patients
For patients, Kadoch’s discoveries could have a far-reaching impact. Because mSWI/SNF complexes, which helps turn genes on and off, are mutated in over 20% of cancers—and serve as critical dependencies in up to 50% of cancers—the potential therapeutic applications for modulating these complexes in different ways span both common and rare cancers, including adult and pediatric patient populations. These complexes dictate the ‘melody’ of gene expression, and at its core, cancer is fundamentally a disease of disharmonious gene expression. By learning to manipulate these complexes, researchers can potentially restore normal gene activity and halt cancer progression.
“This is just the tip of the iceberg,” Kadoch says. “The ability to study these complexes in their native forms and to integrate a suite of powerful methods to probe their functions has changed the game for how we think about targeting cancer.”
From Discovery to Drug Development
These insights from Kadoch and her colleagues have provided a valuable roadmap for new approaches to drug development in this area, according to Doug Cole, MD, Managing Partner of Flagship Pioneering, who helped found Foghorn Therapeutics in 2016.
“When Cigall and I first met to discuss the possibility of creating a company together to build on and translate her science, it was immediately apparent to me that her visionary approach to gene regulation could open vast new opportunities to help patients,” Cole says.
Instead of targeting isolated proteins, scientists could now identify small molecules that engage with the full complexes and their interactions with other proteins and features on chromatin in their natural states. And in the setting of cancer, this work has provided the springboard for cancer cell type-specific targeting.
Carrying the Research Forward
One program emerging from Foghorn targeting the mSWI/SNF complex centers on a SMARCA2-selective inhibitor, developed for cancers with SMARCA4 mutations, which are common in non-small cell lung cancer and other tumor types. SMARCA2 and SMARCA4 are both subunits of the mSWI/SNF complex. Normally, cells can use either one—but when SMARCA4 is missing, cancer cells become dependent solely on SMARCA2 to survive. In cellular and preclinical models, blocking SMARCA2 shuts down cancer cells while largely sparing healthy ones, hopefully limiting unwanted toxicities. The treatment is now being tested in patients through a clinical trial led by Foghorn Therapeutics and Eli Lilly, which began in early 2025.
“We have been successful in drugging targets that others have struggled with, including historically undruggable targets that many biopharmaceutical companies have attempted and failed to drug,” says Adrian Gottschalk, President and Chief Executive Officer of Foghorn. “This is now translating into real momentum and, we believe, the potential to meaningfully change outcomes for patients,” he adds.
Foghorn is now in the clinic with its third small molecule agent based on their platform, and the company continues to build on the scientific insights developed at Dana-Farber.
“It’s incredibly exciting and humbling to see this science move from the lab to the clinic,” Kadoch says. “And it’s a testament to the value of curiosity-driven basic research that can ultimately change lives.”
Team Members
Cigall Kadoch, PhD
Professor of Pediatric Oncology and Meredith and Billy Starr Investigator, Dana-Farber Investigator, Howard Hughes Medical Institute
