Abstract
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.
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Abbreviations
- ALK:
-
Anaplastic lymphoma kinase (Ki-1),anaplastic lymphoma receptor tyrosine kinase
- ARID1A:
-
Actin dependent regulator of chromatin, subfamily f, member 1
- BRAF:
-
V-raf murine sarcoma viral oncogene homolog B
- CDK4, CDK6, EGFR:
-
Epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog
- ERBB2:
-
v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
- ERBB4:
-
Erb-B2 receptor tyrosine kinase 4
- FAT1:
-
FAT atypical cadherin 1
- FGFR1:
-
Fibroblast growth factor receptor 1
- FGFR2:
-
Fibroblast growth factor receptor 2
- FGFR3:
-
Fibroblast growth factor receptor 3
- IDH1:
-
Isocitrate dehydrogenase (NADP(+)) 1
- IDH2:
-
Isocitrate dehydrogenase (NADP(+)) 2
- KEAP1:
-
Kelch like ECH associated protein 1
- KIT:
-
KIT proto-oncogene, receptor tyrosine kinase
- KRAS:
-
KRAS proto-oncogene, GTPase
- MET:
-
MET proto-oncogene, receptor tyrosine kinase
- MYC:
-
MYC proto-oncogene, BHLH transcription factor
- NFE2L2:
-
NFE2 like BZIP transcription factor 2
- NRAS:
-
NRAS proto-oncogene, GTPase
- PDGFRA:
-
Platelet derived growth factor receptor alpha
- PIK3CA:
-
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
- POLD1:
-
DNA polymerase delta 1, catalytic subunit
- POLE:
-
DNA polymerase epsilon, catalytic subuni
- RET:
-
Ret proto-oncogene
- ROS1:
-
ROS proto-oncogene 1, receptor tyrosine kinase
- SETD2:
-
SET domain containing 2, histone lysine methyltransferase
- STK11:
-
Serine/Threonine kinase 11
- TP53:
-
Tumor protein P53
- MET:
-
MET proto-oncogene, receptor tyrosine kinase
- SHOC2:
-
SHOC2 leucine rich repeat scaffold protein
- PP1C:
-
Protein phosphatase 1 catalytic subunit gamma
- HUWE1:
-
HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1
- VCP1:
-
Valosing containing protein 1
- LIFR:
-
LIF receptor subunit alpha
- SCRIBBLE:
-
Scribble planar cell polarity protein
- ZDHHC7:
-
ZDHHC palmitoyltransferase 7
- YES1:
-
YES proto-oncogene 1, Src family tyrosine kinase
- YAP:
-
Yes1 associated transcriptional regulator
- E-CADHERIN:
-
Cadherin 1
- FASN:
-
Fatty acid synthase
- LZTR1:
-
Leucine zipper like post translational regulator 1
- NFE2L2:
-
Nuclear factor erythroid 2-like 2
- ENO1:
-
Enolase 1
- RGS3:
-
Regulator of G protein signaling 3
Funding
This work was supported by generous funding from Julián Santamaría Valiño to the IOR Foundation.,no grant ID
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Giménez-Capitán, A., Olmo-Gónzalez, D., Martínez-Pérez, E. et al. Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRAS G12C NSCLC. Sci Rep (2026). https://doi.org/10.1038/s41598-026-48898-1
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DOI: https://doi.org/10.1038/s41598-026-48898-1
