Exploring the potential of CDK7 inhibition to permanently arrest cancer cells
Bibliographic record
Abstract
Despite the clinical success of some targeted therapies in treating cancer, the response to them is often temporary, due to treatment resistance developing. Therefore, researchers must continue to look for novel ways to treat cancer. A number of groups are developing CDK7 inhibitors as anti-cancer drugs. CDK7 is a protein that has two major roles in cells - regulation of RNA polymerase II-mediated transcription and cell cycle progression as the CDK activating kinase. Both of these cellular processes are often deregulated during oncogenesis. Our collaborators at Imperial College London have developed a novel CDK7 inhibitor, ICEC0942, that is currently in Phase I/II clinical trials. ICEC0942 has been shown to inhibit the proliferation of cancer cell lines, but the mechanism by which it does this has not been previously determined. The work presented in this thesis aimed to understand this better. To establish its mechanism of action, we studied the effects of ICEC0942 on non- transformed RPE1 cells. Our data shows that ICEC0942 induces a permanent cell cycle arrest, with the cells displaying phenotypic characteristics of senescence. This contrasts to a more well-studied CDK7 inhibitor THZ1, which inhibits cell proliferation by inducing apoptosis. The data from a chemogenetic screen with ICEC0942, carried out by collaborators at the University of Montreal, revealed that activation of mTOR signalling was positively correlated with ICEC0942 efficacy. Further experiments confirmed these results by showing that inhibition of the mTOR signalling pathway partially rescued characteristics of senescence induced by ICEC0942 treatment. This was demonstrated in RPE1 cells and MCF7 cells, a breast cancer cell line. From this we hypothesise that ICEC0942 induces senescence by uncoupling cell division and cell growth, and that mTOR signalling plays an important role in this. Our future work will focus on how to use this insight to guide the clinical use of ICEC0942.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".