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An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancerResearch in context

Authors :
Haiyun Wang
Qi Lv
Yue Xu
Zhaoqing Cai
Jie Zheng
Xiaojie Cheng
Yao Dai
Pasi A. Jänne
Chiara Ambrogio
Jens Köhler
Source :
EBioMedicine, Vol 49, Iss , Pp 106-117 (2019)
Publication Year :
2019
Publisher :
Elsevier, 2019.

Abstract

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

Subjects

Subjects :
Medicine
Medicine (General)
R5-920

Details

Language :
English
ISSN :
23523964
Volume :
49
Issue :
106-117
Database :
Directory of Open Access Journals
Journal :
EBioMedicine
Publication Type :
Academic Journal
Accession number :
edsdoj.7bae6cee9c9473ca0b364e56fcd3e09
Document Type :
article
Full Text :
https://doi.org/10.1016/j.ebiom.2019.10.012