Transcriptomic Profiling Characteristics of Immune Infiltration and Antioxidant Pathway in STK11^mutTP53^wtKRAS^mut Lung Cancers

Background KRAS mutations define a molecular subgroup of non-small cell lung cancer (NSCLC). KRAS G12C inhibitors have been approved in clinic, yet with limited efficacy, and inhibitors targeting other KRAS mutation subtypes are under development. Further investigation of cellular and molecular components of KRAS-mutant (KRAS^mut) NSCLC is warranted to understand the disease mechanisms and guide precise treatment.

Methods After histopathological evaluation of tumor specimens from KRAS^mut NSCLC, DNA and RNA were extracted. Comprehensive genomic and transcriptomic profiling of KRAS^mut NSCLC was performed.

Results Next-generation sequencing (NGS) results showed that, Among 162 cases of KRAS^mut NSCLC, subtypes of KRAS mutations included G12C (n=68), G12D (n=33), G12V (n=32), G12A (n=9), G13D (n=6), Q61H/L (n=6) and others (n=8). Frequent co-mutations occurred in TP53, LRP1B, STK11(LKB1), KEAP1, SPTA1, PTPRD, MGA, FAT1, and RBM10. TP53 was the most commonly co-mutated gene (n=94, 58.0%), followed by STK11 (n=47, 29.0%) and dual STK11/TP53 co-mutation (n=15, 9.3%). Based on the co-mutation patterns of KRAS, TP53, and STK11, samples were classified into four groups: KO (KRAS^mut-only, n=36), KP (TP53^mutKRAS^mut, n=79), KL (STK11^mutTP53^wtKRAS^mut, n=32) and KM (STK11^mutTP53^mutKRAS^mut, n=15). The expression of STK11 was low in STK11^mut samples. In KL group, KEAP1 mutation was significantly enriched (P=1.8×10⁻³), NRF2 regulation was activated, gene set enrichment analysis (GSEA) enrichment analysis showed that NRF2 regulation genes were significantly enriched (P=5.6×10⁻⁸), the expression levels of NRF2 regulation related genes such as AKR1C1/2, GCLC, GPX2, GSTP1, NQO1, PGD, SLC7A11, and PRDX1 were significantly higher than those in other groups (P<0.05), the expression level of CD274 was significantly lower than that of other groups (P=4×10⁻⁴), and the immune score was low, showing a cold immune characteristic.

Conclusions STK11^mutTP53^wtKRAS^mut (KL) lung cancer is a unique biological subtype, having biological characteristics of cold immunity, NRF2 anti-oxidation activation and genomic instability. The results provide scientific insight for clinical optimization of precise diagnosis and treatment strategy in KRAS^mut NSCLC.