An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context
Background: KRAS mutations are the most frequent oncogenic aberration in lung adenocarcinoma. KRAS mutant isoforms differentially shape tumour biology and influence drug responses. This heterogeneity challenges the development of effective therapies for patients with KRAS-driven non-small cell lung...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-11-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419306760 |
| _version_ | 1819172526085898240 |
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| author | Haiyun Wang Qi Lv Yue Xu Zhaoqing Cai Jie Zheng Xiaojie Cheng Yao Dai Pasi A. Jänne Chiara Ambrogio Jens Köhler |
| author_facet | Haiyun Wang Qi Lv Yue Xu Zhaoqing Cai Jie Zheng Xiaojie Cheng Yao Dai Pasi A. Jänne Chiara Ambrogio Jens Köhler |
| author_sort | Haiyun Wang |
| collection | DOAJ |
| description | Background: KRAS mutations are the most frequent oncogenic aberration in lung adenocarcinoma. KRAS mutant isoforms differentially shape tumour biology and influence drug responses. This heterogeneity challenges the development of effective therapies for patients with KRAS-driven non-small cell lung cancer (NSCLC). Methods: We developed an integrative pharmacogenomics analysis to identify potential drug targets to overcome MEK/ERK inhibitor resistance in lung cancer cell lines with KRAS(G12C) mutation (n = 12). We validated our predictive in silico results with in vitro models using gene knockdown, pharmacological target inhibition and reporter assays. Findings: Our computational analysis identifies casein kinase 2A1 (CSNK2A1) as a mediator of MEK/ERK inhibitor resistance in KRAS(G12C) mutant lung cancer cells. CSNK2A1 knockdown reduces cell proliferation, inhibits Wnt/β-catenin signalling and increases the anti-proliferative effect of MEK inhibition selectively in KRAS(G12C) mutant lung cancer cells. The specific CK2-inhibitor silmitasertib phenocopies the CSNK2A1 knockdown effect and sensitizes KRAS(G12C) mutant cells to MEK inhibition. Interpretation: Our study supports the importance of accurate patient stratification and rational drug combinations to gain benefit from MEK inhibition in patients with KRAS mutant NSCLC. We develop a genotype-based strategy that identifies CK2 as a promising co-target in KRAS(G12C) mutant NSCLC by using available pharmacogenomics gene expression datasets. This approach is applicable to other oncogene driven cancers. Fund: This work was supported by grants from the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Lung Cancer Research Foundation and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation. Keywords: Pharmacogenomic profiles, KRAS mutations, Lung adenocarcinoma, CSNK2A1, CK2, MEK inhibitor, Silmitasertib, Wnt/β-catenin, EMT |
| first_indexed | 2024-12-22T20:08:35Z |
| format | Article |
| id | doaj.art-a7bae6cee9c9473ca0b364e56fcd3e09 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T20:08:35Z |
| publishDate | 2019-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-a7bae6cee9c9473ca0b364e56fcd3e092022-12-21T18:14:05ZengElsevierEBioMedicine2352-39642019-11-0149106117An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in contextHaiyun Wang0Qi Lv1Yue Xu2Zhaoqing Cai3Jie Zheng4Xiaojie Cheng5Yao Dai6Pasi A. Jänne7Chiara Ambrogio8Jens Köhler9School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Correspondence to: Haiyun Wang, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.School of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaSchool of Life Sciences and Technology, Tongji University, Shanghai 200092, ChinaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Co-Corresponding authors: Jens Köhler and Chiara Ambrogio, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Co-Corresponding authors: Jens Köhler and Chiara Ambrogio, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.Background: KRAS mutations are the most frequent oncogenic aberration in lung adenocarcinoma. KRAS mutant isoforms differentially shape tumour biology and influence drug responses. This heterogeneity challenges the development of effective therapies for patients with KRAS-driven non-small cell lung cancer (NSCLC). Methods: We developed an integrative pharmacogenomics analysis to identify potential drug targets to overcome MEK/ERK inhibitor resistance in lung cancer cell lines with KRAS(G12C) mutation (n = 12). We validated our predictive in silico results with in vitro models using gene knockdown, pharmacological target inhibition and reporter assays. Findings: Our computational analysis identifies casein kinase 2A1 (CSNK2A1) as a mediator of MEK/ERK inhibitor resistance in KRAS(G12C) mutant lung cancer cells. CSNK2A1 knockdown reduces cell proliferation, inhibits Wnt/β-catenin signalling and increases the anti-proliferative effect of MEK inhibition selectively in KRAS(G12C) mutant lung cancer cells. The specific CK2-inhibitor silmitasertib phenocopies the CSNK2A1 knockdown effect and sensitizes KRAS(G12C) mutant cells to MEK inhibition. Interpretation: Our study supports the importance of accurate patient stratification and rational drug combinations to gain benefit from MEK inhibition in patients with KRAS mutant NSCLC. We develop a genotype-based strategy that identifies CK2 as a promising co-target in KRAS(G12C) mutant NSCLC by using available pharmacogenomics gene expression datasets. This approach is applicable to other oncogene driven cancers. Fund: This work was supported by grants from the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Lung Cancer Research Foundation and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation. Keywords: Pharmacogenomic profiles, KRAS mutations, Lung adenocarcinoma, CSNK2A1, CK2, MEK inhibitor, Silmitasertib, Wnt/β-catenin, EMThttp://www.sciencedirect.com/science/article/pii/S2352396419306760 |
| spellingShingle | Haiyun Wang Qi Lv Yue Xu Zhaoqing Cai Jie Zheng Xiaojie Cheng Yao Dai Pasi A. Jänne Chiara Ambrogio Jens Köhler An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context EBioMedicine |
| title | An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context |
| title_full | An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context |
| title_fullStr | An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context |
| title_full_unstemmed | An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context |
| title_short | An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context |
| title_sort | integrative pharmacogenomics analysis identifies therapeutic targets in kras mutant lung cancerresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419306760 |
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