Transcriptomics

Dataset Information

0

Acquired resistance to MEK-CDK4/6 inhibitor combinations in cutaneous melanoma


ABSTRACT: Continuous MEK and CDK4/6 inhibition is effective in pre-clinical models, nevertheless, some tumors acquire resistance that was associated with enhanced phospho S6. To characterize the mechanism mediating the upregulation of mTOR-S6 pathway in these tumors, we performed RNA sequencing and targeted panel sequencing on xenograft tumors that progressed on either MEK plus CDK4/6 inhibitors (ComboR) or control diet. Gene set variance analysis (GSVA) revealed distinct gene expression signatures between the two ComboR tumors indicating heterogeneity. However, one of the 44 shared pathways between ComboR1 and ComboR2 included upregulation of an AKT pathway gene signature. By targeted sequencing and RNA sequencing, we observed high copy number change of NRAS in ComboR1 and a third tumor sample isolated from a continuous MEK inhibitor-intermittent CDK4/6 inhibitor schedule. NRAS was confirmed to mediate increased mTOR-S6 pathway activation suggesting that while distinct mechanisms are employed by melanoma tumors to circumvent MEK plus CDK4/6 inhibition, those resistance pathways eventually converge upon phosphorylation of S6 protein.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111005 | GEO | 2018/04/05

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2012-08-08 | E-GEOD-39984 | biostudies-arrayexpress
2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress
2012-02-01 | GSE35230 | GEO
2012-08-09 | GSE39984 | GEO
2014-10-31 | E-GEOD-51906 | biostudies-arrayexpress
2015-03-11 | PXD000528 | Pride
2021-06-06 | GSE158609 | GEO
2021-06-06 | GSE158608 | GEO
2021-06-06 | GSE158607 | GEO
2014-10-31 | GSE51906 | GEO