Characteristics of tumor microenvironment in <i>STK11</i> ^<i>m</i> <i> TP53 ^m KRAS ^m </i> non-small cell lung cancers and survival outcomes.

Abstract

e20559 Background: KRAS mutations define a molecular subgroup of non-small cell lung cancer (NSCLC). KRAS G12C inhibitors have been approved in clinic and targeting other KRAS mutation subtypes is under development. Further investigation of cellular and molecular components of KRAS -mutant ( KRAS m ) NSCLC is warranted to understand the disease mechanisms and guide precise treatment. Methods: Comprehensive genomic and transcriptomic profiling of KRAS m NSCLC was performed using the Illumina TruSight Oncology 500 kit and TruSeq RNA Exome kit. Tumor mutation burden (TMB) differences among groups were assessed by the Kruskal–Wallis test. Survival curves were estimated using the Kaplan–Meier method and compared by the log-rank test. For RNA-based supervised clustering, we applied an ANOVA F-test to rank genes by their between-group variance relative to within-group variance, and selected the top 200 most discriminatory features. Immune infiltration was inferred using the ESTIMATE algorithm. Results: Among 162 cases of KRAS m NSCLC, TP53 was the most commonly co-mutated gene followed by STK 11 . Based on the co-mutation status of TP53 and STK11 , patients were classified into four groups: KO ( KRAS m -only, n = 31), KP ( TP53 m KRAS m , n = 79), KL ( STK11 m KRAS m , n = 32), and KPL ( STK11 m TP53 m KRAS m , n = 15). KPL patients had the worst overall survival (OS, p = 0.034) of 217 days, and lower tumor mutation burden (TMB, p = 1.54×10 -6 ), lower immune score by ESTIMATE (p = 0.0264), lowest expression of STK11 ( p &lt; 0.001). Compared to KP or KL subgroup, KPL tumors were systematically inhibited regarding the functions of calcium, sodium, potassium and other ion transport channels, and T cell related pathways and the activation of NK-T cells and mast cells were also inhibited. In KPL tumors, NF-κB, TGF-β, mTOR, Wnt signaling pathways were highly enhanced, showing special characteristics of high proliferation, high oxidative phosphorylation and high lipid metabolism in this subgroup. The poor prognosis of KPL patients significantly associated with the high expression of SMOX, SLC7A5, RHOV, MAFK, LBP and NR4A2 genes and the low expression of TRPV2, PIK3CG, P2RX7. Conclusions: KRAS m NSLCLs are highly heterogeneous, and TP53 and STK11 co-alterations could stratify patients into four groups (KO, KP, KL, KPL) with distinct immune landscape and prognosis. STK11 m TP53 m KRAS m (KPL) tumors were specifically highly immune cold, with high proliferation, oxidative phosphorylation, and lipid metabolism and associated with a worst survival. This data may inform further investigation for targeted vulnerabilities of this KPL subgroup.