Excel · study · 2026
Expression profiling of MET TKI resistant Hs746T cells.
Listed in NCBI GEO
MET exon 14 skipping mutations (METΔex14) are oncogenic drivers in ~3-5% of lung cancer, which can be targeted with MET tyrosine kinase inhibitors (TKIs).
Description
The emergence of resistance limits long-term responses and is commonly mediated by secondary genomic alterations. We devised a preclinical strategy to study MET-TKI resistance using a novel dose escalation approach on METΔex14-dependent cancer cells to generate MET-TKI-refractory isogenic counterparts.
Targeted sequencing of resistant clones identified acquired mutations in SPOP and MGA, both antagonists of MYC activity. Further investigation of SPOP and MGA interactomes confirmed MYC as the likeliest target shared between their regulatory networks. SPOP- and MGA-mutant clones exhibited high MYC levels and transcriptomic signatures of MYC activation.
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Ectopic expression of MYC rescued tumor growth in the presence of TKI, while MYC depletion mimicked the cytotoxic effect of TKI treatment, indicating that MYC activity is coupled to MET signaling and MYC is required to mediate drug resistance. Analysis of a clinical cohort of METΔex14-positive lung cancer revealed several cases where acquired MYC pathway alterations mediated resistance to MET-TKIs. These findings collectively converge on MYC as a key pathway in the progression of MET TKI-resistant cancers, and our in vitro data support the strategy of co-targeting MYC and MET to yield more prolonged responses in patients with METΔex14-positive lung cancer.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE298nnn/GSE298399 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298399 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1269073 ncbi.nlm.nih.gov/bioproject/PRJNA1269073 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by array · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · Sequencing 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE298399 | 14 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 (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-array | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| 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 |