Abstract 1817: Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib
Bibliographic record
Abstract
Abstract Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as a first-line treatment against such tumors, but NSCLC tumors often recur with a mutant EGFR (often with a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active aganst both T790M EGFR and the original non-T790M-mutated, oncogenic EGFR. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR mutations T790M and L858R (exon 21). To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1975 cell line for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance. Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected in the presence of 6 and 10 μM osimertinib (one each) or in 5 μM osimertinib plus 10 μM verapamil (3 cell lines). These clonal lines were, respectively, 90-, 95-, 38-, 227-, and 244-fold resistant to osimertinib. The RAD51 inhibitor 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2), which enhances cytotoxicity of several EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2017, doi.org/10.1124/jpet.117.241661), decreased osimertinib-resistance by up to 80% in these cell lines. Sequence analysis indicates that cell line H1975/osi-6b retained the same EGFR sequence as that in the parent cell line. H1975/osi-5b/VPL appears to have undergone epithelial-to-mesenchymal transition. Further analyses of the resistant cell lines are being undertaken. These cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs. Citation Format: Peter J. Ferguson, Mark D. Vincent, James Koropatnick. Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1817.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.003 |
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".