Breast cancer cells as seen under a microscope. (Credit: via )
A new 彩民宝典-led study sheds light on a protein key to controlling how cells grow, proliferate and function and long implicated in tumor development.
The findings, published this week in the journal , could lead not only to new therapies for hard-to-treat cancers, but also inform novel treatments for neurological diseases and rare developmental disorders, the authors say.
鈥淭hese findings could have broad biomedical application,鈥� said lead author Dylan Taatjes, a professor in the Department of Biochemistry.
For decades, scientists have known that the protein Cyclin Dependent Kinase 7 (CDK7) plays an instrumental role in helping all cell types transcribe, or decode, the genetic instructions provided by their DNA.听
As Taatjes explains, each cell contains the same vast library, or genome. But a kidney cell may turn to different sections of that library for instructions than, say, a skin cell or a heart cell. Like a librarian, CDK7 helps ensure that each cell accesses the right instructions at the right time, guiding which genes get flipped on and off.
Dylan Taatjes
While that鈥檚 important during human development and for normal cell function, CDK7 can be exploited by cancer cells to drive runaway growth. In recent years, scientists have discovered that the protein can fuel certain cancers to proliferate out of control, including 鈥渢riple negative鈥� breast cancers, which are more aggressive and don鈥檛 respond well to common treatments.听
That finding has inspired growing interest in the development of so-called 鈥淐DK7-inhibitors鈥� but due to a lack of understanding of what the CDK7 does, early clinical trials have been disappointing.
鈥淲e wanted to find out exactly how it鈥檚 really working inside human cells,鈥� Taatjes said.
To that end, the Taatjes lab teamed up with scientists from two pharmaceutical companies, Syros and Paraza, as well as colleagues in other 彩民宝典 labs, the University of Colorado School of Medicine and the BioFrontiers Institute.
Using sophisticated analytical techniques, basic biochemistry and next-generation genetic sequencing, the team identified, for the first time, the hundreds of specific proteins that CDK7 switches on or off, providing unprecedented insight into its role in cells.
The study also revealed that:听
- CDK7 plays a role in multiple stages of transcription (decoding the genome), shaping what is known as 鈥渢ranscriptional splicing鈥� 鈥� in which unneeded parts of the transcribed genome are pruned away to leave only those necessary for the cellular task at hand. Notably, errors in splicing have been linked to myriad diseases, including blood cancers.
- CDK7 serves as a 鈥渕aster regulator鈥� of other key enzymes, turning them on to further drive transcriptional programs. Defects in the execution of such programs have been linked to cognitive diseases, including Alzheimer鈥檚 disease and rare developmental disorders, including head and facial deformities.
- The function of CDK7 is controlled by the company it keeps. When attached to a larger 10-protein complex, known as TFIIH, it is largely inactive. 听But when it breaks off on its own, its activity ramps way up.
Phase 1 trials are currently underway administering the latest version of CDK7 inhibitors to drug-resistant breast, colorectal, lung, ovarian and pancreatic cancer patients.
The findings of the new study suggest such drugs hold promise, Taatjes said.听
鈥淚n biology, it is widely recognized that cells will compensate by activating other enzymes if one specific enzyme is inhibited,鈥� he said, explaining the mechanism behind drug resistance. 鈥淥ur results suggest that CDK7 inhibitors could have distinct therapeutic advantages, given that they would not only block CDK7, but would impact the function of other enzymes.鈥�
The research could also lead to next-generation therapeutics, which鈥攊nstead of silencing the protein completely鈥攚ould target it only in its liberated, most active phase. This could result in more selective inhibitors that would be less damaging to healthy cells, with fewer side effects.
And because of its many roles in shaping how human cells develop and function, other applications may be possible.
鈥淐ancer is an obvious application but it is by no means the only one,鈥� Taatjes said.
