Abstract 895: Activating transcription factor 3 (ATF3) down-regulation correlates with platinum resistance in non-small cell lung cancer (NSCLC).
Bibliographic record
Abstract
Abstract Background: NSCLC is the most common cause of cancer-related death. Platinum-based chemotherapy is the mainstay of treatment, but a variety of mechanisms lead to platinum-resistance. ATF3 is a transcription factor, activated in response to a wide variety of stress signals including DNA damage and hypoxia. We recently demonstrated a role for ATF3 as an important regulator of platinum-induced cytotoxicity. In this study, we hypothesize that ATF3 expression correlates with platinum-sensitivity/resistance in NSCLC. Methods: ATF3 induction was examined by Western blots and real-time RT-PCR in isogenic sets of platinum- sensitive (S) or induced resistant (R) NSCLC cell lines. A 1200 compound library was screened to identify platinum-sensitizers in both sets of cell lines. Complete RNA sequencing (RNA-seq) was performed in parental (S) and resistant (R) derived cell lines comparing expression patterns of either untreated or platinum treated cells. Similarly, platinum R and S tumors were identified by screening NSCLC patients’ clinical records and expression patterns compared with RNA-seq analysis. Results: Both mRNA and potein levels of ATF3 were induced 35-120 fold (mRNA) by cisplatin treatment in S cell lines, but only 1-12 fold (mRNA) in the corresponding R lines. The 1200 compound library screen of FDA approved compounds identified several commonly used chemotherapeutic agents as sensitizers of platinum cytotoxicity, as well as vorinostat, a histone deacetylase inhibitor that sensitized only S but not R cell lines. An analogue of this agent, M344, enhanced ATF3 induction and cisplatin cytotoxicity in the S lines but not in the R lines. Comparing RNA-seq results of the S and R lines revealed up-regulation of GADD45A, ATF3 and DDIT3/CHOP in the S but not R cell lines. Comparing samples of S and R NSCLC tumors by RNA-seq demonstrated ATF3 to be among the five genes significantly up-regulated in the S tumors compared to the R tumors. Conclusions: Stress-induced ATF3 is correlated with platinum-sensitivity in NSCLC cells. Tumor ATF3 levels represent a potential predictive marker of response to platinum-based treatment in NSCLC. Revealing the mechanism of ATF3 induction by platinum may lead to the identification of novel platinum-sensitizing therapeutic targets. Citation Format: Jair Bar, Ivan Gorn-Hondermann, Reid Stephanie, Patricia Moretto, Iris Shiran, Shlomit Jessel, Marina Perelman, Eyal Heller, Iris Kamer, Inbal Daniel-Meshulam, Glenwood D. Goss, Jim Dimitroulakos. Activating transcription factor 3 (ATF3) down-regulation correlates with platinum resistance in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 895. doi:10.1158/1538-7445.AM2013-895
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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".