An Integrative Pharmacogenomics Analysis Identifies Therapeutic Targets in KRAS-Mutant Lung Cancer

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Background: KRAS mutations are the most frequent oncogenic aberration in lung adenocarcinoma. Due to differences in protein structure and GTPase activity, KRAS mutant isoforms shape tumor biology and therefore may influence the treatment response in non-small-cell lung cancer. This heterogeneity challenges the development of effective targeted therapies for KRAS-driven lung cancer. Methods: Here, we systematically investigated MEK/ERK inhibitors sensitivity for different KRAS mutant isoforms. Then we developed an integrative pharmacogenomics analysis to identify potential targets in lung cancer with KRAS(G12C) mutation, the most frequent aberration in patients with primary or metastatic KRAS mutant non-small cell lung cancer. We further validated our prediction by siRNA-mediated gene knockdown and TOPFlash reporter assay. Findings: Our computational analysis identifies casein kinase 2A1 (CSNK2A1) as a mediator of MEK inhibitor resistance in KRAS(G12C) mutant cells which is not observed in cells with non-KRAS(G12C) mutations and in those harboring other oncogenic drivers as e.g. activating mutations in EGFR, BRAF, or NRAS. Knockdown of CSNK2A1 reduces proliferation, inhibits Wnt/I²-catenin signalling and increases the anti-proliferative effect of selumetinib in KRAS(G12C) mutant lung cancer cells. Interpretation: Our study suggested that accurate patients stratification will be necessary in order to observe significant benefit upon CK2 inhibition - alone or in combination - in a subset of patients with a favorable intratumoral genetic context. We provide a promising approach towards developing precision treatments for various subtypes of KRAS mutant lung cancer. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (31571363, 31771469, and 81573023 to HW) the National key research and development program of China (2017YFC0908500 to HW), the Lung Cancer Research Foundation (to CA) and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation (70111755 to JK). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: Not required.