Session highlights transcriptional CDKs as cancer target
Accurate control of gene expression is essential for normal development. Deregulation of transcription invariably results in human pathologies, such as cancer.
During the Advances in Diagnostic and Therapeutics session, Targeting Transcriptional Cyclin-Dependent Kinases in Cancer, three experts discussed transcriptional cyclin-dependent kinases (CDKs) and how dysregulation of the transcription cycle plays a role in cancer. Their presentations were discussed in more detail during a live panel discussion. Both will be available to registrants through June 21, 2021.
Ricky W. Johnstone, PhD, of the Peter MacCallum Cancer Centre, discussed work from his lab looking at distinct roles of different transcriptional CDKs in regulating gene expression, tumor cell growth, and survival.
Aberrant transcription is a hallmark of cancer, Johnstone said. In his lab, they think about transcription more as a cycle rather than in a linear view. This cycle is similar to the cell cycle with distinct checkpoints and is regulated by CDK and cognate cyclin pairs. This transcription cycle may be deregulated in cancer.
If that is true, and CDKs are enzymes, then they can be targeted with small molecules. It is no surprise that the cyclins at the beginning of the transcription cycle, CDK7 and CDK9, rank high in cancer-dependency maps.
Johnstone’s lab has done work looking at small molecules to target CDK9 in MYC-driven malignancies or MLL-rearranged AML. Research has shown that the introduction of small molecules that inhibit CDK9, such as dinaciclib, can induce tumor cell death.
Further studies showed that CDK9-mediated RNA polymerase II (RNAPII) pause-release in the cycle is functionally opposed by protein phosphatase 2A (PP2A) complex. PP2A is recruited to transcription-pausing sites by INTS6, and loss of INTS6 confers resistance to CDK9 inhibition. INTS8 was also identified as another key component for recruitment of PP2A.
Johnstone presented more details on loss of INTS6/PP2A and its role in turnover of CDK9 substrates and CDK9 induced transcriptional pausing. He also discussed a study pairing a CDK9 inhibitor with a PP2A agonist that showed synergy between the drugs, and extended survival of mice treated with the combination.
Rani George, MD, PhD, Dana Farber Cancer Institute, spoke about targeting transcriptional vulnerabilities in cancer. This is proposed through inhibiting CDK that have important roles in transcription. She said CDKs are divided in two classes, those involved in cell cycle progression and those involved in transcriptions.
George discussed her research on use of CDK7 to disrupt the transcription of amplified MYCN in neuroblastoma cells, as well as targeting CDK12 in cancers with genomic instability.
This ongoing research has shown that development of selective transcriptional CDK inhibitors do form tractable targets and can be efficacious in certain types of cancer, for example those that are transcription-addicted or genomically unstable.
“We also know that CDKs are able to compensate for one another and we need to learn more about their functions and their redundant states,” George said. “When you have highly selective inhibition, we find that combination therapies for example CDK7 plus BRD4 inhibitors or CDK12 and PARP inhibitors are good strategies.”
Geroge said that still more work needs to be done for optimization of preparations that can be used in the clinic in terms of the mode of administration as well as bioavailability and plasma clearance.
Ali Shilatifard, PhD, Northwestern University Feinberg School of Medicine, discussed principles of epigenetics and chromatin in development and human disease. During his presentation, he detailed his lab’s work in trying to understand chromosomal translocations of the mixed-lineage leukemia (MLL) gene.
Studies had shown that several frequent translocation partners of MLL were found to coexist in what was named the super elongation complex (SEC) that included known transcription elongation factors such as ELL and P-TEFb.
They have shown that the function of SEC is to make slow polymerases transcribe faster and wondered if translocation within the SEC family affected the rate of transcription elongation. It is possible to get rid of SEC in these cancers and make fast polymerases slow. Could this be a therapeutic approach?
They found that that peptidomimetic lead compound KL-1 and its structural homolog, KL-2, could disrupt the cyclin T1-AFF4 interaction within SEC and that SEC inhibitors attenuated SEC-dependent rapid transcriptional responses. SEC was required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuated that response.
This SEC inhibition delays tumor progression in a mouse model of an MYC-driven cancer, indicating that small molecular disruption of SEC could be used as a targeted therapy in these cancers, Shilatifard said.
Finally, Shilatifard discussed work exploring whether CDK9 functioning is involved in rapid transcriptional induction.
During the panel discussion, presenters fielded many questions about transcription and CDK9 and CDK7, including one question about what worked best experimentally for inhibiting CDKs.
Johnstone noted that CDK inhibitors come in different forms. There are ATP-competitive inhibitors, covalent transcriptional inhibitors, and small molecules. George and Shilatifard also discussed the use of CDK degraders and oxygen inducible systems to specifically knockdown not only CDKs but other components of the complex.
“The other system you could think about is an analogue-sensitive system where you mutate the kinase itself so that you could use analogues of ATP to specifically inhibit the kinase activity of that CDK,” Johnstone said. “There is really a suite of tools available experimentally to try and determine the specific effects of inhibiting the CDK versus perhaps the off-target effects.”