Abstract A122: The tyrosine kinase inhibitor MP470 inhibits RAD51-mediated homologous recombination and increases tumor cell radio- and chemosensitivity
Bibliographic record
Abstract
Abstract MP470 is a tyrosine multi-kinase inhibitor whose targets include PDGFR, c-Kit and c-Met and is being tested as a single agent in Phase I clinical trials. In pre-clinical drug testing in vitro, we noted a reduction in the expression of RAD51, a key protein involved in the homologous recombination (HR) pathway of DNA double strand break (DSB) repair. We therefore tested whether MP470 can actually decrease HR function and thereby act as a radio- and chemosensitizer through a novel mechanism of action. We conducted qRT-PCR, Western blots, flow cytometric, inter-chromosomal DNA-dsb rejoining assays, subnuclear DSB recruitment and clonogenic survival using H1299 lung carcinoma cells with and without MP470 treatment. These cells incorporate a DR-GFP system which directly assesses HR by quantitative flow cytometry. As a single agent, MP470 treatments of 0.1 to 25 uM (24h) reduced RAD51 protein expression in H1299 cells in a dose-dependent manner. The ICD50 based on clonogenic assays was 0.66 uM; 1–2.5uM treatments reduced RAD51 levels by 50–60% with little effect on cell cycle distribution. This rules out that reduced RAD51 expression was secondary to cell cycle redistribution and decreased S phase following MP470 treatment. The same treatments reduced functional HR by 50% based on the DR-GFP assay. Using whole cell treatments with ionizing radiation (IR; 6Gy) and Mitomycin C (MMC) or UV microbeam sub-nuclear irradiation, we observed decreased expression and formation of RAD51 complexes at sites of DNA damage in MP470-treated (2.5uM) cells. Consistent with this finding, treatment of H1299 cells with 1 or 2.5uM MP470 led to significantly increased cell killing to IR and MMC (a drug that preferentially kill HR-defective cells) based on clonogenic assay. Confirmatory studies are ongoing with other cancer cell lines. We conclude that MP470 may have an additional mode of action by interfering with HR in cancer cells. Given that many cancers acquire radio- and chemoresistance and over-express RAD51, MP470 may be a novel drug to overcome RAD51-mediated therapeutic resistance. MP470 warrants further testing alone, or in combination with radiotherapy and chemotherapy, in pre-clinical and clinical efficacy studies with the development of HR-associated biomarkers. (Supported by funds from SuperGen, a Terry Fox Hypoxia Project Program Grant and a CCS Reseach Scientist award to RGB.). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A122.
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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".