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Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome
Ana Alcaraz-Sanabria1, Esther Cabañas Morafraile2,3, Gonzalo Fernández-Hinojal2
1Translational Oncology Laboratory, Centro Regional de Investigaciones Biomédicas, Castilla-La Mancha University (CRIB-UCLM), Albacete, Spain.
Abstract:
Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, as it has previously been observed with other inhibitors. Recently, new immune therapeutics, including vectorized compounds with antibodies or modulators of the host immune response, have demonstrated clinical activity. By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered immunologic correlates of outcome that were clearly de-regulated in this particular tumor type and we matched them with immune cell populations. In conclusion, our article describes membrane proteins and immunologic correlates that could be used to better select and optimize current therapies.
Insights
Novel therapies targeting K-RAS-mutant non-small cell lung cancer (NSCLC) are emerging. This study identifies specific membrane proteins and immune markers to improve treatment selection and optimize outcomes for NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Sotorasib shows promise for K-RAS-mutant non-small cell lung cancer (NSCLC), but resistance is anticipated.
- Emerging immune therapeutics, including vectorized compounds, demonstrate clinical activity in NSCLC.
- There is a need for strategies to overcome treatment resistance in K-RAS-mutant NSCLC.
Purpose of the Study:
- To identify novel surface membrane proteins selectively expressed in K-RAS-mutant NSCLC for targeted therapy.
- To discover immunologic correlates of outcome associated with K-RAS-mutant NSCLC.
- To match identified immune correlates with specific immune cell populations for therapeutic optimization.
Main Methods:
- Analysis of large-scale datasets, including The Cancer Genome Atlas (TCGA).
- Identification and selection of genes encoding differentially expressed surface membrane proteins.
- Interrogation of immunologic data to find outcome correlates and their association with immune cells.
Main Results:
- Identified CLDN10 and TMPRSS6 as genes encoding surface membrane proteins with clear differential expression in K-RAS-mutant NSCLC.
- Discovered specific immunologic correlates of outcome that are dysregulated in K-RAS-mutant NSCLC.
- Successfully matched these immune correlates with distinct immune cell populations.
Conclusions:
- CLDN10 and TMPRSS6 represent potential targets for vectorizing novel therapies in K-RAS-mutant NSCLC.
- Identified immunologic correlates and immune cell populations can aid in selecting and optimizing current therapies.
- This research provides a foundation for developing more effective and personalized treatment strategies for NSCLC.
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