Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS Mutations in Non-Small Cell Lung Cancer
Biagio Ricciuti1, Jieun Son2, Jeffrey J Okoro2
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Purpose:
Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking.
Experimental Design:
We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non-small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations.
Results:
In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors.
Conclusions:
This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.
Insights
KRAS mutations in lung adenocarcinoma show significant heterogeneity. This study reveals isoform-specific vulnerabilities and identifies distinct genomic alterations, suggesting tailored therapeutic strategies for KRAS-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Activating missense mutations in KRAS are primary drivers in lung adenocarcinoma (LUAD).
- Significant heterogeneity exists among KRAS isoforms, with limited understanding of isoform-specific therapeutic vulnerabilities.
Purpose of the Study:
- To compare oncogenic properties and therapeutic actionability of different KRAS-mutant isoforms.
- To analyze clinicopathologic and genomic data for KRAS mutation allele-specific features in non-small cell lung cancer (NSCLC).
Main Methods:
- Developed an isogenic cell-based platform for comparing KRAS-mutant isoforms.
- Analyzed genomic and transcriptomic data from 3,560 NSCLC patients.
- Utilized in vitro and in vivo models to assess isoform-specific properties and therapeutic responses.
Main Results:
- Identified distinct biochemical, biological, and oncogenic properties for different KRAS isoforms.
- Demonstrated differential sensitivity to MEK inhibitors, with KRAS G12C and Q61H mutants showing higher sensitivity.
- Found enrichment of STK11, ATM, and KEAP1 mutations in specific KRAS-mutant LUADs, with unique transcriptomic profiles for each isoform.
Conclusions:
- KRAS isoforms exhibit significant heterogeneity in genomic alterations and gene expression.
- Stratification based on KRAS alleles is crucial for designing future clinical trials and personalized therapies.
