Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells
Abstract 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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03370-4 |
| _version_ | 1819054674650595328 |
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| author | Yu-xiang Wang Xu Zhang Qing-yang Ma Lan-dian Hu Xi Zhang Yi Wang Lan Xu Chun-hao Yang Cun Tan Xiang-yin Kong Jian Ding Ling-hua Meng |
| author_facet | Yu-xiang Wang Xu Zhang Qing-yang Ma Lan-dian Hu Xi Zhang Yi Wang Lan Xu Chun-hao Yang Cun Tan Xiang-yin Kong Jian Ding Ling-hua Meng |
| author_sort | Yu-xiang Wang |
| collection | DOAJ |
| description | Abstract 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 G12S 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. |
| first_indexed | 2024-12-21T12:55:23Z |
| format | Article |
| id | doaj.art-e86fa4e218ec48b6b0441df9763b31ff |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-21T12:55:23Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e86fa4e218ec48b6b0441df9763b31ff2022-12-21T19:03:22ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111310.1038/s41419-020-03370-4Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cellsYu-xiang Wang0Xu Zhang1Qing-yang Ma2Lan-dian Hu3Xi Zhang4Yi Wang5Lan Xu6Chun-hao Yang7Cun Tan8Xiang-yin Kong9Jian Ding10Ling-hua Meng11Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDivision of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Nutrition and Health, Chinese Academy of SciencesShanghai Institute of Nutrition and Health, Chinese Academy of SciencesDivision of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDivision of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDivision of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Nutrition and Health, Chinese Academy of SciencesUniversity of Chinese Academy of SciencesDivision of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract 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 G12S 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.https://doi.org/10.1038/s41419-020-03370-4 |
| spellingShingle | Yu-xiang Wang Xu Zhang Qing-yang Ma Lan-dian Hu Xi Zhang Yi Wang Lan Xu Chun-hao Yang Cun Tan Xiang-yin Kong Jian Ding Ling-hua Meng Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells Cell Death and Disease |
| title | Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells |
| title_full | Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells |
| title_fullStr | Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells |
| title_full_unstemmed | Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells |
| title_short | Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells |
| title_sort | adaptive resistance to pi3kα selective inhibitor cyh33 is mediated by genomic and transcriptomic alterations in escc cells |
| url | https://doi.org/10.1038/s41419-020-03370-4 |
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