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Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma
Ke Liu1, Jintao Guo1, Kuai Liu1
1Department of Translational Medicine, Medical College of Xiamen University, Xiamen 361102, China; Center for Biomedical Big Data Research, Medical College of Xiamen University, Xiamen 361102, China.
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.
Insights
KRAS-mutant lung cancer heterogeneity is linked to smoking. Researchers identified two subtypes with distinct features, enabling targeted drug discovery and sensitivity prediction for better treatment outcomes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- KRAS-mutant lung adenocarcinomas (LUAD) exhibit significant heterogeneity, complicating drug discovery.
- This heterogeneity is particularly prevalent in smokers, a key demographic for LUAD.
Purpose of the Study:
- To investigate the heterogeneity of KRAS-mutant LUAD.
- To identify distinct subtypes within KRAS-mutant LUAD.
- To discover subtype-specific drugs and biomarkers for treatment sensitivity prediction.
Main Methods:
- Integrated multiplatform data from patients and cell lines to identify LUAD subtypes.
- Characterized the molecular and immunological features of each subtype.
- Performed drug screening and analyzed genotype-phenotype correlations for drug sensitivity prediction.
Main Results:
- Identified two patient subtypes (PS1 and PS2) and corresponding cell line subtypes (CS1 and CS2).
- PS1 showed high smoking-related mutational activity, low tumor-infiltrating lymphocytes (TILs), and STK11/KEAP1 co-mutations.
- PS2 exhibited high smoking-related methylation activity, high TILs, and increased KRAS dependency, with identified drugs like cytarabine and a BTK inhibitor showing subtype-specific efficacy.
Conclusions:
- KRAS-mutant LUAD heterogeneity is driven by smoking-related genomic and epigenomic alterations.
- Features like immunogenicity, KRAS dependency, and STK11/KEAP1 co-mutations can serve as predictive biomarkers for drug sensitivity.
- This subtype-specific approach holds promise for advancing personalized medicine in LUAD treatment.
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