MRAS, SHOC2, PP1C and YAP1 mRNA level variations at 72 hours of targeted therapy in KRAS G12C-mutant non-small cell lung cancer cell lines
Year: 2026
Type: article
Abstract: Background: The treatment of KRAS G12C-mutant non-small cell lung cancer (NSCLC) has become a dominant field of ongoing translational research. Still, the effect of the first KRAS G12C inhibitor, sotorasib, or next-generation inhibitors, such as fulzerasib, in KRAS-mutant NSCLC patients is short-lived. Although the objective response rate is encouraging, the median progression-free survival is 12.5 months with fulzerasib combined with cetuximab (an EGFR monoclonal antibody), and treatment efficacy is reduced when TP53, STK11, or KEAP1 mutations co-exist. In KRAS G12C sensitive cell lines, such as NCI-H358, early up regulation of MRAS and YAP1 occurs following therapy with sotorasib. We aim to assess variations in the mRNA levels of the MRAS-SHOC2-PP1C complex components that are associated with MAPK reactivation, as well as those of related genes, chiefly HUWE1 and VCP1, and among others, YAP1, the wild-type RAS isoforms HRAS and NRAS, MET, and ERFFI1, a negative regulator of EGFR.Methods: NCI-H358, H23, and H2030 were treated with either sotorasib or fulzerasib and in combination with cetuximab. RNA isolation was performed and NCounter and Digital Analyzer (NanoString Technologies) was used targeting 21 transcripts from gene expression analysis (MET; KRAS; MRAS, SHOC2, PP1C, HUWE1, VCP1, LIFR, SCRIBBLE, ZDHCC7, YES, YAP1, E-cadherin, FASN, LZTR1, NFE2L2, ENO1, RGS3, NRAS and HRAS). The assessment was performed at baseline and 72 hours after each treatment: Comparisons between groups were conducted using the Kruskal-Wallis and paired comparison with t-test. Student’s t-test was used to calculate P values for gene expression analysis.Results: For the sensitive NCI-H358, significant upregulation of MRAS, SHOC2, PP1C, YAP1, as well as HUWE1 and VCP1, was observed after 72 hours of treatment with sotorasib and cetuximab. Either sotorasib or fulzerasib, in combination with cetuximab, upregulate ERFFI1. In the less sensitive H23, PP1C, HRAS, and MET were the most significantly overexpressed genes after 72 hours of treatment. In the resistant H2030 cell line, MRAS mRNA levels were upregulated with either sotorasib or fulzerasib or in combination with cetuximab. YAP1 was detected to be phosphorylated at Y357 by Western blot analysis.Conclusions: The RAS pathway can be reactivated by MRAS, SHOC2, PP1C, and YAP1. Although cetuximab can upregulate ERFFI1 in NCI-H358 cells, the elevation of such transcripts warrants further investigation to determine whether to target individual components of the MRAS-SHOC2-PP1C complex or YAP1. MET mRNA levels could also be examined to identify KRAS G12C-mutant tumors in which MET may be upregulated. The effects of STK11 and/or KEAP1 co-mutations require further research.
Source: Annals of Translational Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224122631