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

EBioMedicine. 2018 Oct:36:196-208. doi: 10.1016/j.ebiom.2018.09.034. Epub 2018 Sep 27.

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.

Keywords: Drug sensitivity prediction; KRAS subtypes; KRAS-mutant lung adenocarcinoma; Smoking-related methylation signature; Smoking-related mutational signature; TIL-associating score.

MeSH terms

  • Adenocarcinoma of Lung / diagnosis*
  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor*
  • Cell Line, Tumor
  • DNA Copy Number Variations
  • DNA Methylation
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Profiling
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Molecular Targeted Therapy
  • Mutation*
  • Prognosis
  • Proto-Oncogene Proteins p21(ras) / genetics*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)