Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells Journal Article
| Authors: | Korkut, A.; Wang, W.; Demir, E.; Aksoy, B. A.; Jing, X.; Molinelli, E. J.; Babur, Ö; Bemis, D. L.; Sumer, S. O.; Solit, D. B.; Pratilas, C. A.; Sander, C. |
| Article Title: | Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells |
| Abstract: | Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs. © 2015, Korkut et al. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; human cell; polymerase chain reaction; phenotype; cell viability; protein kinase inhibitor; protein protein interaction; enzyme activity; proteomics; gene transfer; algorithm; myc protein; melanoma cell; dna fingerprinting; computer simulation; computer model; mathematical computing; b raf kinase; protein microarray; cost; phosphatidylethanolamine binding protein; human; article; bromodomain inhibitor |
| Journal Title: | eLife |
| Volume: | 4 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2015-08-18 |
| Start Page: | e04640 |
| Language: | English |
| DOI: | 10.7554/eLife.04640 |
| PROVIDER: | scopus |
| PMCID: | PMC4539601 |
| PUBMED: | 26284497 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
