Abstract 383P
Background
KRAS mutations are the most common oncogenic driver in NSCLC, with KRAS G12C being the most frequently subtype. While KRAS G12C-mutated (mt) tumors generally exhibit a better response to immunotherapy (ICI) compared to other KRAS mutations, the underlying biological mechanisms remain understood.
Methods
We analyzed RNA sequencing data comparing G12C and non-G12C tumors, focusing on differentially expressed genes (DEGs) and their potential implications for ICI response. RNA extraction was performed from a total of 17 paraffin cases with KRAS mutation (7 G12C and 10 non-G12C). Gene expression analysis was performed with the Illumina Exome Panel - Enrichment Oligos Only (ref 20020183). Data on DEGs are based on significant unadjusted p-values and enrichment analysis on significant adjusted p-values.
Results
Patients’ characteristics are described in table. We identified several DEGs in KRAS G12C tumors, including SOX2, PTPRZ1, AQP3, and DHRS9, with overexpression, and CCL21, MMP1, SFTPB, and CYP11A1 among the suppressed genes. AQP3 and DHRS9 are associated with cellular metabolismand oxidative stress, which may influence the tumor microenvironment and immune cell activity. Downregulation of CCL21 may reduce immune infiltration by reducing the recruitment of Tregs and myeloid-derived suppressor cells while suppressed MMP1, involved in extracellular matrix remodeling, could reflect differences in tumorstroma interactions. Enrichment analysis revealed activation of pathways related to oxidative phosphorylation and retinol metabolism in G12C-mt tumors supporting cytokine secretion and regulation of T cell differentiation. Although the sample size (n) is small, the results are preliminary and intended as a proof of concept.
Table 383P| N (%) | KRAS G12C (n=7) | KRAS no G12C (n=10) |
| Sex | ||
| Female | 2 (28.6%) | 5 (50%) |
| Male | 5 (71.4%) | 5 (50%) |
| Median age | 68 | 68 |
| Tobacco | ||
| Former | 4 (57.1%) | 6 (60%) |
| Current | 2 (28.5%) | 4 (40%) |
| No smoker | 1 (14.33%) | 0 (0%) |
| Ml liver | 0 (0%) | 2 (20%) |
| Ml CNS | 2 (28.5%) | 3 (30%) |
| Stage | ||
| [-111 | 2 (28.4%) | 2 (20%) |
| IV | 5 (71.4%) | 8 (80%) |
| Co-mutations | ||
| TP53 | 2 (28.5%) | 8 (80%) |
| STK11 | 0 (0%) | 2 (20%) |
| KEAP1 | 0 (0%) | 3 (30%) |
| PD-L1 | ||
ConclusionsOur results suggest differences in the expression of immune-related genes between KRAS G12C and non-G12C mutations, which may partly explain variations in immunotherapy response. FundingHas not received any funding DisclosureL. Masfarre Pinto: Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer; Financial Interests, Personal, Other, Travel Suport: AstraZeneca. S. Clave: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Roche, Takeda, Novartis, Janssen; Financial Interests, Personal, Advisory Board: Lilly. A. Taus Garcia: Financial Interests, Personal, Invited Speaker: GSK, GSK, Takeda, Roche, AstraZeneca, Pfizer, Eisai; Financial Interests, Personal, Advisory Board: Sanofi, BMS, AstraZeneca. B. Bellosillo Paricio: Financial Interests, Personal, Advisory Board: Menarini; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Merck Serono, Roche, Thermofisher, Pfizer, BMS; Financial Interests, Personal, Expert Testimony: Janssen; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. P.F. Simoes Da Rocha: Other, Personal, Other, Congress and travel: MSD, BMS, AstraZeneca, Kyowa Kirin, Roche. E. Arriola Aperribay: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, AstraZeneca, Pfizer, Boehringer Ingelheim, Lilly, Takeda. All other authors have declared no conflicts of interest. This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used. For more detailed information on the cookies we use, please check our Privacy Policy.
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