Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity
| Autor: | Min Lu, Anika Agarwal, Peter S. Winter, Kevin H. Lin, Esther Liu, Kris C. Wood, Merve Cakir, Grace R. Anderson, Ryan S. Soderquist, Lorin Crawford |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Bh3 mimetic Science bcl-X Protein General Physics and Astronomy Computational biology Biology Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences Cell Line Tumor Neoplasms medicine Animals CRISPR RNA Messenger lcsh:Science Gene Sulfonamides Multidisciplinary Dose-Response Relationship Drug Cas9 Cancer General Chemistry Bridged Bicyclo Compounds Heterocyclic medicine.disease Antineoplastic Agents Phytogenic 3. Good health 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Cell culture Cancer cell lcsh:Q Systematic mapping |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-13 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-05815-z |
| Popis: | While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics. Dependency of diverse cancers on specific BCL-2 family members and their combinations is unknown. Here they perform drug screening and find most cell lines to be dependent on at least one combination of BCL-2 family members, and using a CRISPR screen find BCL-w and BFL-1 to mediate resistance to BH3 mimetics |
| Databáze: | OpenAIRE |
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