Abstract PR12: Targeting CDK7/9 in basal pancreatic cancer
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) is classified into two distinct subtypes, classical and basal, with the basal subtype predicting worse survival in patients. We hope that with a deeper understanding of the biology that drives these subtypes, we can identify novel subtype-specific therapies. We recently described a novel finding that basal PDAs are uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9. Additionally, we identified that Sirtuin 6 histone deacetylase (SIRT6) expression levels correlate with PDA subtype, showing that basal PDA is low in SIRT6 expression and classical PDA is high through analysis of hundreds of human PDA tumors. Furthermore, we uncovered an important mechanism by which SIRT6 regulation of the integrated stress response (ISR) can control sensitivity of PDA to CDK7/9 inhibitors. By using a variety of in vitro drug assays, genetic manipulation experiments, immunofluorescence, cycloheximide chase experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDA, we were able to show that SIRT6 regulates activating transcription factor 4 (ATF4) protein stability. Therefore, SIRT6 high/classical PDA has a constitutively active ISR, enabling it to recover and survive the stress of CDK7/9 transcriptional inhibition. On the other hand, basal PDA has low SIRT6 which promotes ATF4 protein instability and a nonfunctional ISR, therefore CDK7/9 transcription inhibition leads to apoptosis. Furthermore, we found that similar to intrinsic resistance, acquired resistance to CDK7/9 inhibitors occurs through the loss of basal state drivers and that restoration of these genes re-sensitizes cells to CDK7/9 inhibition. Importantly, this work highlights the role of chromatin modifiers in regulating PDA subtypes and sensitivity to CDK7/9 inhibitors. PDA subtypes have very distinct chromatin landscapes. We have found that classical PDA maintains its epithelial cell state through chromatin regulators like the SETDB1 heterochromatin complex and more specifically the KRAB-Zinc Finger protein ZNF274. Loss or gain of ZNF274 can induce a cell state change in which classical PDA loses its epithelial characteristics and becomes more mesenchymal in nature. Excitingly, this sensitizes cells to CDK7/9 inhibition. Thus, our work demonstrates the importance of cell state and subtype in therapeutic response to CDK7/9 inhibitors in pancreatic cancer. Citation Format: Sita Kugel, Nithya Kartha, Jessica E. Gianopulos, Zach Schrank, Sarah M. Cavender, Stephanie Dobersch, Notta Faiyaz, David H. Price, Andrew C. Hsieh, Sunil R. Hingorani. Targeting CDK7/9 in basal pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR12.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
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 teacher head, 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".