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Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRAS G12C NSCLC
Ana Giménez-Capitán1,2, Daniel Olmo-Gónzalez2,3, Elizabeth Martínez-Pérez1
1Pangaea Oncology Lab, Dexeus University Hospital, Barcelona, Spain.
Abstract:
Advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations can be treated with selective inhibitors, however progression-free survival remains limited. Resistance has been associated with co-mutations in TP53, STK11, and KEAP1, persistent plasma KRAS G12C, and activation of the MRAS-SHOC2-PP1C pathway with downstream YAP1 signaling. We evaluated the expression of MRAS-SHOC2-PP1C and YAP1-related genes in KRAS G12C mutant NSCLC. Messenger RNA levels of twenty genes were quantified using nCounter in tumor samples from 98 NSCLC patients, including KRAS G12C (n=23), KRAS non-G12C (n=24), and KRAS wild-type (n=51) cases. Longitudinal plasma samples from ten KRAS G12C patients treated with selective inhibitors were analyzed at baseline, day 3, week 6, and week 12. Eight genes (NFE2L2, NRAS, KRAS, ENO1, SHOC2, VCP1, LIFR, and MRAS) were differentially expressed in KRAS G12C compared with KRAS wild-type tumors (p<0.05). LIFR, KRAS, and MET were differentially expressed in KRAS non-G12C tumors. Among 30 KRAS-mutant patients, high LIFR expression was associated with improved survival. In plasma, twelve genes were consistently detected, and SHOC2, YAP1, LZTR1, RGS3, and ZDHHC7 were significantly upregulated at week 6. Low tumor LIFR expression was associated with poorer survival, supporting its potential as a prognostic biomarker and highlighting the feasibility of plasma-based gene expression monitoring.
Insights
Targeted therapy for KRAS G12C non-small cell lung cancer (NSCLC) shows promise, but resistance is an issue. This study identifies LIFR as a potential prognostic biomarker for improved survival in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutations is treatable with targeted inhibitors.
- Limited progression-free survival and resistance mechanisms, including co-mutations and pathway activation (MRAS-SHOC2-PP1C, YAP1), necessitate further research.
- Understanding gene expression in KRAS-mutant NSCLC is crucial for identifying biomarkers and improving treatment outcomes.
Purpose of the Study:
- To evaluate the expression of MRAS-SHOC2-PP1C and YAP1-related genes in NSCLC with different KRAS mutation statuses.
- To identify potential prognostic biomarkers for survival in KRAS-mutant NSCLC.
- To assess the feasibility of plasma-based gene expression monitoring in patients treated with KRAS G12C inhibitors.
Main Methods:
- Quantification of messenger RNA levels for twenty genes in tumor samples from 98 NSCLC patients (KRAS G12C, KRAS non-G12C, KRAS wild-type) using nCounter technology.
- Longitudinal analysis of plasma samples from ten KRAS G12C-mutant NSCLC patients treated with selective inhibitors at multiple time points.
- Statistical analysis to identify differentially expressed genes and their association with survival and treatment response.
Main Results:
- Eight genes, including MRAS, were differentially expressed in KRAS G12C tumors compared to KRAS wild-type tumors (p<0.05).
- High LIFR (Leukemia Inhibitory Factor Receptor) expression in KRAS-mutant tumors correlated with improved patient survival.
- Plasma analysis revealed significant upregulation of SHOC2, YAP1, and other genes at week 6 of treatment, indicating potential for non-invasive monitoring.
Conclusions:
- LIFR expression in NSCLC tumors may serve as a prognostic biomarker, with high levels indicating better survival.
- The study highlights the feasibility of monitoring gene expression changes in plasma during targeted therapy for NSCLC.
- Further investigation into the MRAS-SHOC2-PP1C-YAP1 pathway and LIFR could lead to improved therapeutic strategies for KRAS-mutant NSCLC.
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