Abstract B06: ING2 loss sensitizes KRAS-mutated NSCLC to WEE1 inhibition through regulation of CHK1 expression
Bibliographic record
Abstract
Abstract ING2 (Inhibitor of Growth 2) is a tumor-suppressor gene involved in chromatin acetylation whose loss has been observed in nearly 60% of NSCLC. The loss of ING2 expression has been associated with the progression of tumor cells from G1 to S phase, replication stress and genomic instability. The intra-S and the G2-M phase checkpoints are mainly regulated by the cell cycle tyrosine kinase WEE1. Therefore, we hypothesized that the loss of ING2 expression could sensitize NSCLC to the WEE1 inhibitor MK-1175, according to a synthetic lethality model. In silico analysis of the cancer gene dependency map (shRNAi Achilles library v.2016) was used to explore gene interactions with ING2. Antiproliferative effects of drugs were tested in vitro with AlamarBlue and MTT assays in a panel of NSCLC cells lines with varied mutational status. Multiple functional approaches were taken to decrease ING2 expression in RAS-mutated NSCLC cell lines (si-RNA, LNA-gapmer, and CrispR-Cas9). Pharmacologic inhibition of ING2 epigenetic functions was achieved using the HDAC inhibitor SAHA. Cell cycle and apoptosis analysis were performed using flow cytometry according to a BrdU-Pi and Annexin V-PI protocols, respectively. Compusyn software was used to model MK-1775 and SAHA drug interaction. NSCLC cell lines with mutant RAS that expressed high levels of ING2 protein were more resistant to the antiproliferative effect of MK-1775 than similar lines with low levels of ING2. Colony formation assays were consistent with these results. Multiple functional assays reproducibly showed that downregulation of ING2 expression increased MK-1775 sensitivity in vitro. Similar results were obtained with pharmacologic disruption of ING2 from the HDAC-SIN3A complex using SAHA, where disruption conferred a higher antiproliferative effect to MK-1775. Interestingly, combination treatment induced cell cycle progression and synergic cell death through apoptosis in RAS-mutated cell lines nondeficient for ING2. Since the synergistic effect of SAHA and WEE1 inhibitor was shown to be dependent on CHK1 activity in a previous report, we checked whether ING2 and CHK1 expression could be linked. Using public database and functional assays, we indeed find that ING2 downregulation represses CHK1 transcription through a mechanism that remains to be elucidated. Collectively, these findings demonstrate that inhibition of WEE1 by MK-1775 could represent a therapeutic approach to more effectively target ING2-deficient RAS-mutated NSCLC. Moreover, HDAC inhibitors targeting ING2 epigenetic functions synergize with MK-1775, possibly through regulation of CHK1 transcription. Consequently, this combination therapy could also be a promising strategy in ING2-proficient RAS-mutated NSCLC. Citation Format: Charles Ricordel, Subash Thalappilly, Jérome Archambeau, Angela Chan, Nancy Nixon, Benoît Desrues, Gwyn Bebb, Karl Riabowol, Rémy Pedeux. ING2 loss sensitizes KRAS-mutated NSCLC to WEE1 inhibition through regulation of CHK1 expression [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B06.
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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 | 0.000 | 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".