Abstract C92: DNA methylating combi-molecule ZRS1 induces p53 and blocks the epidermal growth factor (EGFR)-activated pathways in EGFR-expressing human tumor cells: Relationship to O6-methylguanine DNA methyltransferase (MGMT) status
Bibliographic record
Abstract
Abstract The combi-targeting concept seeks to design single molecules that combine an EGFR tyrosine kinase inhibitor with a DNA damaging agent. One such molecule, ZRS1 contains an EGFR tyrosine kinase targeting quinazoline moiety and a methyltriazene-based DNA-damaging function capped with an acetoxymethyloxy group that stabilizes the 1,2,3-triazene chain. Here, we analyzed the DNA damage response, the MAPK and the PI3K pathways in response to the dual action of ZRS1. We also determined whether its mixed EGFR-DNA targeting property could enhance its potency in tumor cells expressing the O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that confers resistance to methylating agents. The growth inhibitory potency of ZRS1 was tested in a panel of 8 human tumor cell lines with varied levels of EGFR and MGMT. ZRS1 was more potent than the clinical methylating agent temozolomide (TEM) in all the cell lines tested, including the lung cancer (A549, A427 and Calu-1), colon cancer [HT29, HCT116 and HCT116 (p53−/−)], and breast cancer cell lines (MDA-MB-468 and MDA-MB-231), regardless of their MGMT status. However, its potency was in the same range as or less than ZD1839, a single-targeted EGFR inhibitor, against MGMT-proficient cells. In the MGMT-deficient cells or MGMT-proficient cells in which MGMT levels were depleted with O6-benzylguanine, its potency was superior to that of ZD1839 or TEM. ZRS1 exhibited IC50 of 0.5 µM in the A427 cell line, a value that was 25-fold lower than that of TEM, 12-fold lower that of ZD1839 and 15-fold lower than that equi-toxic and equimolar combinations of ZD1839+TEM. The two lung cancer cell lines A549 (MGMT+) and A427 (MGMT−) were selected for analyzing the cell signaling pathways underlying the growth inhibitory effect induced by the dual effects of ZRS1. The results showed that: 1. ZRS1 strongly inhibited EGFR phosphorylation in both cell lines and this translated into inhibition of ERK1/2, AKT, Bad S112 and Bad S136 phosphorylation in both cell lines 2. ZRS1 inflicted significant levels of genomic DNA damage and induced p53 in a dose-dependent manner in both cell lines. Likewise Bax and GADD45 were also induced in both cell lines. The results in toto suggest that in the presence of MGMT, ZRS1 primarily acts as an EGFR inhibitor with no significant effect of its DNA damaging component. In contrast, in the absence of MGMT, its ability to (a) activate the p53 pathway (b) block the MAPK and PI3K pathways, translates into significant cell-killing. Further studies with plasmid transfection either to knockdown endogenous MGMT or express exogenous MGMT are ongoing to elucidate the mechanism underlying the suppression of the potency of ZRS1 by MGMT. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C92.
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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 | 0.000 |
| 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) | 0.003 | 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".