380. INTEGRATIVE TRANSCRIPTOMIC AND FUNCTIONAL ANALYSIS OF CHEMOTHERAPY RESISTANCE IN ESOPHAGEAL ADENOCARCINOMA
Bibliographic record
Abstract
Abstract Background Gastroesophageal Adenocarcinoma (GEA) is one of the most lethal malignancies in North America with a 5-year survival of <20%. Currently, the standard-of-care treatment for GEA patients is docetaxel-based triplet chemotherapy. However, around 40% of patients are innately resistant to chemotherapy, and half of the initial responders develop acquired resistance during treatment. There is an urgent need to understand the molecular mechanisms driving chemotherapy resistance and identify alternative therapeutic options. Methods Primary tumor tissue was collected from 29 GEA patients to generate patient-derived organoids (PDOs). PDOs were treated with chemotherapy, and the cell viability was measured using Cell Titer Glo. A 3200-compound library was screened at a single concentration (1uM) on three chemo-resistant PDOs. Compounds that showed efficacy in all three lines were then tested in combination with chemotherapy to evaluate their synergistic effects. Single-cell RNA sequencing (scRNA) was performed for 8 chemo-sensitive and 16 chemo-resistant patients. We conducted a transcriptomic analysis to identify markers that are differentially expressed in the two groups. Pathway analysis was performed using Gene Set Enrichment Analysis. Results Cell viability of the PDOs obtained from chemo-resistant patients was significantly higher than that of chemo-sensitive patients. High-throughput (HTP) screening revealed 21 drugs that showed efficacy in all three PDOs, including inhibitors for ribosomes, oxidative phosphorylation (OXPHOS) pathway, and NFkB pathway. Correspondingly, scRNA analysis indicated that chemo-resistant patients have up-regulated ribosome biosynthesis and OXPHOS pathways, as well as increased expression of CCND1, which is a downstream target of the NFkB pathway. Furthermore, the IGF1R inhibitor Ceritinib demonstrated a significant synergistic effect when combined with chemotherapy, with a synergy score of 19.9. Conclusions GEA organoids recapitulate the chemotherapy response of patients, making them an ideal model for ex-vivo drug testing. Integrative analysis of the HTP functional screening and scRNA sequencing data revealed ribosome biogenesis, OXPHOS pathway and IGF-1R as potential therapeutic targets to overcome chemoresistance in GEA.
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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 | 0.001 |
| Bibliometrics | 0.001 | 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) | 0.002 | 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 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".