Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells

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...

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Published in:	Cell death & disease 2021-01, Vol.12 (1), p.85-85, Article 85
Main Authors:	Wang, Yu-Xiang, Zhang, Xu, Ma, Qing-Yang, Hu, Lan-Dian, Zhang, Xi, Wang, Yi, Xu, Lan, Yang, Chun-Hao, Tan, Cun, Kong, Xiang-Yin, Ding, Jian, Meng, Ling-Hua
Format:	Article
Language:	eng
Subjects:	1-Phosphatidylinositol 3-kinase Adaptations c-Myc protein Esophageal cancer Esophagus Extracellular signal-regulated kinase Genomes Kinases MAP kinase Mutation Myc protein Point mutation Protein kinase Ribonucleic acid RNA Squamous cell carcinoma Whole genome sequencing Xenografts
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Summary:	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, HRAS mutation was found in KYSE180C cells. Overexpression of HRAS in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRAS 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.
ISSN:	2041-4889 2041-4889