Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRAS G12C NSCLC.

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.