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Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

ABSTRACT: BACKGROUND:KRAS-mutant lung adenocarcinomas (LUADs) are heterogeneous and frequently occur in smokers. The heterogeneity of KRAS-mutant LUAD has been an obstacle for the drug discovery. METHODS:We integrated multiplatform datatypes and identified two corresponding subtypes in the patients and cell lines. We further characterized the features of these two subtypes and performed drug screening to identify subtype-specific drugs. Finally, we used the defining features of the KRAS subtypes for drug sensitivity prediction. FINDINGS:Patient-Subtype 1 (PS1) was characterized by increased smoking-related mutational signature activity, a low tumor-infiltrating lymphocyte (TIL)-associating score and STK11/KEAP1 co-mutations. Patient-Subtype 2 (PS2) was characterized by an increased smoking-related methylation signature activity, a high TIL-associating score and increased KRAS dependency. The cell line subtypes faithfully recapitulated all the patients' features. Drug screening of the two cell line subtypes yielded several potential candidates, such as cytarabine and enzastaurin for Cell-line-Subtype 1 (CS1) and a BTK inhibitor QL-XII-61 for Cell-line-Subtype 2 (CS2). The defining features, such as smoking-related methylation signature, were significantly associated with the sensitivity to several drugs. INTERPRETATION:The heterogeneity of KRAS-mutant LUAD is associated with smoking-related genomic and epigenomic aberration along with other features such as immunogenicity, KRAS dependency and STK11/KEAP1 co-mutations. These features might be used as biomarkers for drug sensitivity prediction. FUND: This research was funded by the Young Scientists Fund of the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, China and the Education and Research Foundation for Young Scholars of Education Department of Fujian Province, China.

SUBMITTER: Liu K

PROVIDER: S-EPMC6197714 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

Liu Ke K Guo Jintao J Liu Kuai K Fan Peiyang P Zeng Yuanyuan Y Xu Chaoqun C Zhong Jiaxin J Li Qiyuan Q Zhou Ying Y

EBioMedicine 20180927

<h4>Background</h4>KRAS-mutant lung adenocarcinomas (LUADs) are heterogeneous and frequently occur in smokers. The heterogeneity of KRAS-mutant LUAD has been an obstacle for the drug discovery.<h4>Methods</h4>We integrated multiplatform datatypes and identified two corresponding subtypes in the patients and cell lines. We further characterized the features of these two subtypes and performed drug screening to identify subtype-specific drugs. Finally, we used the defining features of the KRAS sub ...[more]

PMID: 30268834

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Project description:Background: Lung adenocarcinoma (LUAD) is a life-threatening malignant tumor, contributing for the largest cancer burden worldwide. Tumor microenvironment (TME) is composed of various immune cells, stromal cells and tumor cells, which is highly associated with the cancer prognosis and the response to immunotherapy, in which macrophages in TME have been revealing a potential target for cancer treatment. In this study, we sought to further explore the role of macrophages in LUAD progression and establish a risk model related to macrophages for LUAD. Methods: We explored immune-related pathways that might be affected by counting positively associated genes in macrophages. Molecular typing was also constructed by mining macrophage-associated genes with prognostic value through COX regression and other analyses. RiskScore prognostic models were constructed using lasso regression and stepwise multifactorial regression analysis. The differences on clinical characteristics among three subtypes (C1, C2, and C3) and RiskScore subtypes were analyzed in TCGA dataset. Immunological algorithms such as TIMER, ssGSEA, MCP-Counter, ESTIMATE, and TIDE were used to calculate the level of difference in immune infiltration between the different subtypes. The TCGA mutation dataset processed by mutect2 was used to demonstrate the frequency of mutations between different molecular subtypes. Finally, nomograms, calibration curves, and decision curves were created to assess the predictive accuracy and reliability of the model. Results: The C1 subtype demonstrated the best prognostic outcome, accompanied by higher levels of immune infiltration and lower mutation frequency, while the majority of patients in the C1 subtype were women under 65 years of age. Myeloid-derived suppressor cell (MDSC) scores were higher in the C3 subtype, suggesting a more severe immune escape, which may have contributed to the tumor evading the immune system resulting in a poorer prognosis for patients. In addition, our RiskScore prognostic model had good predictive accuracy and reliability. Conclusion: This paper provides a study of macrophage-related pathways, immunosuppression, and their mechanisms of action in lung cancer, along with targets for future treatment to guide the optimal treatment of lung cancer.

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Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

Publications

Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

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