Omics · study · 2026
NSCLC KRAS G12C MUTANT CELLS ARE DEPENDENT ON MUC1-C FOR RESISTANCE TO KRAS INHIBITORS II
Listed in NCBI GEO
Treatment of NSCLC KRAS G12C mutant tumors with targeted KRAS inhibitors, such as sotorasib and adagrasib, is invariably associated with the emergence of acquired resistance.
Description
The mechanisms responsible for resistance to these agents have largely remained unclear. We report that patients with NSCLC KRAS G12C tumors expressing increased levels of the MUC1 gene exhibit decreases in overall survival in response to sotorasib and adagrasib.
In investigating the basis for this finding, we found that exposure of NSCLC KRAS G12C mutant cells to these agents induces expression of the oncogenic MUC1-C/M1C protein. We show that M1C induction is STAT1 dependent and that targeting M1C increases sensitivity to sotorasib. Studies of sotorasib-resistant (SR) cells further reveal upregulation of M1C chromatin levels in association with activation of the epithelial-mesenchymal transition (EMT).
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Mechanistically, M1C drives NF-kB p65-mediated induction of the ZEB1 EMT-TF. Furthermore, targeting M1C NF-kB ZEB1 signaling suppresses EMT and sotorasib resistance. Having identified this M1C dependence, we demonstrate that targeting M1C with an antibody-drug conjugate (ADC) is effective against sotorasib-resistant cells growing in vitro and as tumor xenografts.
These findings identify M1C as a major effector of sotorasib resistance and as a target for ADC treatment of patients with refractory NSCLC KRAS G12C mutant tumors.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE315nnn/GSE315054 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315054 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1394932 ncbi.nlm.nih.gov/bioproject/PRJNA1394932 ↗
project · from NCBI GEO
- PubMed 42557306 pubmed.ncbi.nlm.nih.gov/42557306 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 65%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE315054 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |