Written by: Beth Dougherty
Medically Reviewed By: Loren Walensky, MD, PhD
In the rare event that an elevator cable breaks, modern buildings have additional fail-safe mechanisms. For example, counterweight and mechanical brakes prevent the car from plummeting to the ground.
Similarly, cells have fail-safe mechanisms to prevent them from death under stress, according to new research from the lab of Dana-Farber investigator Loren Walensky, MD, PhD. A well-known process in cells keeps pro-death proteins at bay. Walensky found a secondary mechanism that thwarts cell-death proteins at ground zero, where they do physical damage that kills the cell. This new discovery, published recently in Cell, could lead to the discovery of medicines capable of tipping cancer cells closer to death.
“We’ve uncovered an entirely new way that our cells control the machinery that causes their self-destruction,” says Walensky. “The findings expand the paradigm for how life-and-death decisions are governed inside our cells and provide new opportunities to develop drugs for diseases such as cancer.”
The first anti-cancer medicine to target pro-survival proteins, called venetoclax, was approved by the US Food and Drug Administration in 2020. Venetoclax unleashes cell death proteins in cancer cells by blocking a key cell-survival protein called BCL-2, which inactivates pro-death proteins.
The science behind BCL-2 that led to drugs like venetoclax was done at Dana-Farber more than two decades ago in the lab of the late Stanley Korsmeyer, MD, who was also Walensky’s mentor. Walensky’s new research represents two decades of effort building upon those early discoveries.
Deep roots of discovery
For a long time, Walensky and others in the field knew that a protein called BAX, which instigates cell death, self-assembles when activated. Individual BAX monomers, which are single entities, join to form an oligomer, a structure made of many BAX units. That structure induces cell death by landing on the surface of the cell’s power plant, the mitochondria, where it self-assembles and punches through the membrane to disable the cell’s source of energy.
The field also knew that pro-survival proteins, like BCL-2, keep BAX from being activated and assembled. Such proteins are exploited in many cancers to keep cancer cells alive. Venetoclax specifically blocks BCL-2 to unleash BAX and tip cancer cells closer to death.
That, most researchers thought, was that.
“There was a notion that once BAX self-associates, there’s no more regulation,” says Walensky. “It’s the point of no return.”
Walensky remained curious. He wanted to know more about the chemical and structural properties of this BAX oligomer. Progress was incremental, but about five years ago, he began to gain traction on the problem using tools that enabled the team to stabilize and study the structure.
A multi-pronged secondary blockade
Through a series of experiments focused on the BAX oligomer, evidence of a secondary fail-safe mechanism working against cell death began to emerge. Walensky’s team, which included co-first authors Catherine Newman, MD, PhD, a former graduate student in the lab, and Micah Gygi, a current graduate student, and several collaborators, discovered that the mechanism is governed by a distinct configuration of cell survival proteins.
They first saw that a protein in the BCL-2 protein family, called BCL-w, forms a dimer, two BCL-w proteins joined together. This dimer, they found, sits on the surface of the mitochondrial membrane and is prepared to fight against BAX in multiple ways.
The dimer can dismantle an assembled BAX oligomer and then dislodge BAX proteins from the mitochondrial membrane surface. It also can puff the membrane outward in a way that makes it harder for BAX to puncture. The opposing effects of these structures on the curvature of the mitochondrial membrane was a striking finding of the study.
“We found that there’s a new frontier downstream from the established pathway that can still regulate BAX beyond the point of no return,” says Walensky. “Anti-apoptotic proteins don’t only ‘catch’ activated BAX monomers, they can also take on a different form to disarm the active killing machine itself.”
A therapeutic vision
This newly discovered cell survival mechanism has the potential to be a target for novel therapeutics. Walensky envisions blocking BCL-2 family survival proteins in ways that disable this fail-safe mechanism to better kill treatment-resistant cancer cells.
More research is needed to bring this idea to fruition. Walensky and his team plan to gain a deeper understanding of the structures involved and how they interact. That kind of information could help the team and their collaborators home in on ways to disrupt those interactions – and potentially disrupt cancer in an entirely new way.