How a focus on fundamentals is powering new cancer treatments

Key Takeaways: 

• HHMI Investigator Cigall Kadoch and her team have spent a decade discovering and characterizing mammalian SWI/SNF (also called BAF) chromatin remodeling complexes — molecular machines that open strands of compacted DNA to help control which genes are turned on and off.  

• The lab’s research has uncovered key information about the structure and components of these complexes, how they are assembled, how they navigate on DNA, and how their disruption leads to disease.  

• These insights are providing a blueprint for the design and development of new small-molecules — and potentially clinical-grade drugs —targeting BAF complexes to treat a wide range of diseases, including adult and pediatric cancers.  

HHMI Investigator Cigall Kadoch was a graduate student studying a relatively obscure group of proteins— the mammalian SWI/SNF or BAF chromatin remodeling complex — when, seemingly overnight, it was thrust into the spotlight.  

With the advent of high-throughput genetic sequencing, Kadoch and other scientists worldwide started to find that BAF complexes — which help control which genes are turned on or off — were very frequently mutated in cancer and neurodevelopmental disorders.   

“I’ll never forget the weeks in which nearly every day, in every major journal, paper after paper emerged reporting that the genes encoding the subunits of this understudied complex were actually among the most frequently mutated in cancer,” Kadoch says. “And this was a huge surprise because the number of labs studying this complex were far fewer than labs studying other gene sets established to play roles in cancer, such as those for kinases or cell signaling pathways. Very few labs were really studying this.” 

The discoveries set off a frenzy of research, with groups running to develop drugs to target these complexes. But Kadoch knew there were still major gaps in what scientists understood about these chromatin remodelers, which she thought could stifle drug development, leading her to pursue a different strategy.  

Kadoch and her newly established lab at the Dana-Farber Cancer Institute stepped back to address these key gaps, aiming to build a solid foundation for future progress. The team worked to figure out the building blocks of the complexes themselves — how they assemble, what forms they take, and where and how they act on DNA — all of which were unknown. 

“We knew we had to invest in a challenging but much needed dissection,” Kadoch says. “And I do think that has proven to be an important decision.” 

Starting From the Beginning to Understand Chromatin Remodeling Complexes 

Chromatin remodeling complexes change how DNA is packaged in the nucleus, opening and closing the tightly wrapped strands of compacted DNA to help control which genes are expressed.  

While researchers had studied these complexes in simple systems like yeast and fruit flies, there were very few labs investigating them in human cells, and researchers had little idea what the complexes looked like or how they worked.  

The Kadoch Lab started out by developing systems to purify BAF complexes directly from human cells, enabling them to study their makeup and assembly in detail for the first time.  

They discovered that there are more than a thousand different possible configurations of the complex, each made up of different combinations of protein subunits, even in a single cell. These combinations vary in different types of cells, enabling the complexes to carry out distinct actions for regulating gene expression.  

The lab is now focusing on understanding the purpose of these different configurations, and how the different complexes are directed where to go, what to do, and at what levels to perform their remodeling activities.  

“That’s a huge goal of our lab, to figure out the molecular logic and the mechanistic underpinnings of why evolution, from yeast to humans, duplicated and diversified so many of these genes, leading to unparalleled combinatorics,” Kadoch says. “If this is governing much of human biology, and runs awry this frequently in disease, figuring out that molecular logic comprehensively, will be one of the biggest things we can do.” 

Discovering the BAF Complex Navigation System 

In cancer, BAF complexes are often misdirected to the wrong places on chromatin, meaning they sit over and activate the wrong genes — a finding that prompted the team to examine how these complexes are directed to specialized locations on DNA in the first place. 

Earlier this year, Kadoch and her team found the complexes are guided to locations by precise interactions with transcription factors — proteins that bind to specific DNA sequences and turn genes on or off.  

They discovered a region on the BAF complex that serves as a docking platform, helping the complex to latch onto various transcription factors. The transcription factors then guide the complexes to the right locations on chromatin so they can get to work. This interaction is important both in normal development and in some cancers, where it can fuel the targeting of BAF complexes to cancer-promoting genes, turning them on and propelling the cancer cell growth.    

The docking platforms, called SWIFT domains, are specific to different versions, or paralogs, of the BAF complex “SMARCD” subunits — a family of three proteins that resulted from genetic duplication and divergence through evolution. By developing small molecules to specific SWIFT domains and their interactions, researchers may be able to disrupt BAF’s role in cancer without affecting its important actions in healthy cells.  

“The more molecular detail we have about mechanisms such as this, the more we can set out to alter certain features of the complex to break certain activities specifically, rather than inhibiting its activity summarily” says Kadoch. “Because this complex is so critical in so many diseases, we believe that if we can work out the precise mechanistic underpinnings, we can succeed in contributing a powerful basic science foundation for — and potentially even driving forward ourselves — an entirely new class of therapeutics for a wide range of human diseases.”