Cancer drugs that inhibit CDK7 rapidly shut down pathways responsible for cell proliferation within minutes.
For organs to develop, grow, and regenerate, cells must divide and multiply, a process known as proliferation. However, when this process becomes dysregulated, it can lead to uncontrolled cell growth and the development of cancer.
New research from CU Boulder, published in Science Advances, provides groundbreaking insight into the role of a mysterious enzyme called CDK7 in regulating this process. The study reveals that experimental cancer drugs targeting CDK7 can rapidly, within minutes, disrupt gene expression pathways that fuel cell proliferation across a wide range of tissues.
“This work addresses a long-standing mystery surrounding an enzyme critical for regulating the cell cycle and cell proliferation,” said senior author Dylan Taatjes, a professor in the Department of Biochemistry. “Not only does it help us understand a fundamental biological process important for development, it also has broad therapeutic applications.”
Understanding an enigma
For decades, cancer researchers and pharmaceutical companies have eyed cyclin-dependent kinase (CDK7) with interest due to its role as a “master regulator” of cell proliferation. CDK7 does this in two ways: It switches on other enzymes known as kinases, including CDKs 1, 2, 4, and 6, which kick-start cells to divide and multiply. It also regulates gene expression in ways that, until now, have remained unclear. The new study found that it controls the function of proteins called transcription factors, which influence when and how genes are expressed.
While CDK7 is critical for normal development, certain cancers, including aggressive and hard-to-treat “triple negative” breast cancers, hijack this process to drive runaway growth.
In recent years, several companies have developed CDK7 inhibitors that, in clinical trials, have worked to slow tumor growth. But it’s not entirely clear how they do this. The drugs have serious side effects, and in clinical trials, they have fallen short of killing tumors entirely.
To better understand how this master regulator works, Taatjes teamed up with Robin Dowell, a professor of Molecular, Cellular and Developmental Biology; Taylor Jones, then a graduate student in biochemistry; and colleagues at CU Boulder’s BioFrontiers Institute.
The researchers applied a CDK7-inhibitor provided by Syros Pharmaceuticals and already used in clinical trials to cancerous human tissue cells. Then they used sophisticated computational techniques to watch, essentially in real time, what happened next.
They found that within 30 minutes, a core set of transcription factors that turn on genes that prompt cells to proliferate was uniformly shut down. In other experiments, this same set of transcription factors was found to be consistently on in all proliferating cell lines tested. This included 79 cell lines, mostly from human cancers, representing 27 different tissue types.
This points, for the first time, to a universal mechanism by which CDK7 controls human cell proliferation, said Taatjes.
“We found that the second that you inhibit CDK7, all of these core transcription factors shut off at once, stopping proliferation in its tracks,” said Taatjes.
Smothering cancer promoters
The research team points to one particular protein that, like a blanket thrown on a patch of growing flames, seems to smother all those transcription factors at once when CDK7 is inhibited. The protein, retinoblastoma protein 1 (RB1), is well known as a key tumor suppression gene whose normal function is often compromised by cancer. But efforts to target RB1 with medication have been largely unsuccessful.
“This study reveals that CDK7 controls RB1 function—a finding that could open doors to new ways of therapeutically targeting RB1,” said Taatjes.
Meanwhile, CDK7’s other role—of kick-starting enzymes that nudge cells to divide and multiply—is also blocked by the inhibitor they tested, but this occurs more slowly and is not dependent on the core set of transcription factors.
Taken together, these findings suggest that it may be possible to develop new therapies that disable some of the enzyme’s disease-causing functions rapidly, while leaving its beneficial roles intact.
“Instead of, essentially, using a sledgehammer to shut down all CDK7 activities, it could be that you could shut down just one branch of its activities that is more important for tumor proliferation while minimally disrupting normal cell function,” said Taatjes.
The result: a more precise cancer killer that inflicts less collateral damage.
Reference: “TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network” by Taylor Jones, Junjie Feng, Olivia Luyties, Kira Cozzolino, Lynn Sanford, Jenna K. Rimel, Christopher C. Ebmeier, Grace S. Shelby, Lotte P. Watts, Jessica Rodino, Nisha Rajagopal, Shanhu Hu, Finn Brennan, Zachary L. Maas, Sydney Alnemy, William F. Richter, Adrian F. Koh, Nora B. Cronin, Ameya Madduri, Jhuma Das, Elliot Cooper, Kristin B. Hamman, John P. Carulli, Mary A. Allen, Sabrina Spencer, Abhay Kotecha, Jason J. Marineau, Basil J. Greber, Robin D. Dowell and Dylan J. Taatjes, 28 February 2025, Science Advances.
DOI: 10.1126/sciadv.adr9660
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