| Added by | pmartino |
|---|---|
| Group name | EquipePM |
| Item Type | Journal Article |
| Title | Rational development of synergistic combinations of chemotherapy and molecular targeted agents for colorectal cancer treatment |
| Creator | Tosi et al. |
| Author | Diego Tosi |
| Author | Esther Pérez-Gracia |
| Author | Salima Atis |
| Author | Mélissa Gabanou |
| Author | Christel Larbouret |
| Author | Marta Jarlier |
| Author | Caroline Mollevi |
| Author | Adeline Torro |
| Author | Maguy Del Rio |
| Author | Pierre Martineau |
| Author | Céline Gongora |
| Abstract | BACKGROUND: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan. METHODS: Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice. RESULTS: Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies. CONCLUSION: Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity. |
| Publication | BMC cancer |
| Volume | 18 |
| Issue | 1 |
| Pages | 812 |
| Date | Aug 13, 2018 |
| Journal Abbr | BMC Cancer |
| Language | eng |
| DOI | 10.1186/s12885-018-4712-z |
| ISSN | 1471-2407 |
| Library Catalog | PubMed |
| Call Number | IMPACT: 3.288 |
| Extra | IMPACT: 3.288 PMID: 30103709 PMCID: PMC6090616 |
| Tags | Aminopyridines, Animals, Benzimidazoles, Camptothecin, Cell Proliferation, collaboration, Colorectal Neoplasms, Drug Resistance, Neoplasm, Drug Synergism, HT29 Cells, Humans, mabimprove, MAP Kinase Kinase 1, Mice, Molecular Targeted Therapy, Morpholines, original, Phosphokinome, private, Protein Kinase Inhibitors, selection, Signal Transduction, siric, Synergistic effect, Xenograft Model Antitumor Assays |
| Date Added | 2018/08/21 - 08:38:04 |
| Date Modified | 2021/03/05 - 10:43:44 |
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