Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells
| Autor: | Chunhao Yang, Lan Xu, Landian Hu, Xiangyin Kong, Qingyang Ma, Yi Wang, Yu-xiang Wang, Xu Zhang, Linghua Meng, Jian Ding, Xi Zhang, Cun Tan |
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| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Morpholines Immunology Mice Nude mTORC1 Gene mutation Biology Transfection medicine.disease_cause Article Piperazines Transcriptome Mice Cellular and Molecular Neuroscience Cell Line Tumor medicine Animals Humans Pyrroles lcsh:QH573-671 Protein kinase A Protein Kinase Inhibitors Cell Proliferation Mutation lcsh:Cytology Kinase High-Throughput Nucleotide Sequencing Oncogenes Genomics Cell Biology Cancer therapeutic resistance Cancer research Esophageal Squamous Cell Carcinoma Signal transduction |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 1, Pp 1-13 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance. |
| Databáze: | OpenAIRE |
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