GEO series

Temporal dynamics of signaling and transcription underlying early adaptation to oncogenic BRAF inhibition in melanoma

GSE252781 Homo sapiens (human) RNA-seq (gene expression) 13 samples Submitted 2024/03/25 Platform GPL16791

At a glance

RNA-seq (gene expression) · human · 13 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Homo sapiens (human)
Topic: MelanomaThis series is part of our curated briefing on it.
Samples: 13 samples: 13 samples, each with a distinct title — no replicated groupsGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.

Summary (written by the submitters)

Despite the recent remarkable progress of targeted therapies for the clinical management of many cancers, response rates remain lower than desired and long-term response durability is often poor due to drug resistance. A major contributor to treatment failure is drug-induced cellular adaptation to therapy, whereby systems-level reprogramming permits a drug-tolerant phenotype that may gradually lead to cell cycle re-entry and portend relapse.

Read the full summary ↓

Drug adaptation is known to rapidly implicate complex signaling and transcriptional regulatory networks, but the scale and temporal dynamics of these remodeling events have yet to be fully resolved. Here, we used mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a drug-tolerant human BRAF-mutant melanoma model. By enriching specific phospho-motifs associated with mitogenic kinases, we were able to detect and monitor thousands of protein phosphorylation sites over a three-day period of drug treatment, followed by a six-day drug holiday to characterize the plasticity of the adaptive response. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent phosphorylation events, and a clear delineation between three distinct phase transitions toward drug tolerance, which was almost completely reversible following drug removal. Through measuring the time evolution of large-scale networks, we were able to exploit phosphoproteome and transcriptome dynamics to infer kinetically-defined regulatory modules, revealing a concerted response to oncogenic BRAF inhibition involving cellular metabolism, RNA processing, and mitogenic signaling that demonstrated strong agreement with prior knowledge. The adaptive response to BRAF inhibition was dominated by a compensatory induction of SRC-family kinase (SFK) signaling, which we found to be at least partially driven by impaired redox homeostasis and accumulation of reactive oxygen species – providing a fine degree of temporal, mechanistic, and phosphorylation site-specific context to an important axis in tumor cell survival. This induction sensitized cells to co-treatment with an SFK inhibitor, and combination therapy significantly outperformed single-agent BRAF inhibition across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the high translational potential for measuring the temporal dynamics of signaling and transcription networks under therapeutic challenge.

This dataset

Open GSE252781 in finder → Find more human RNA-seq datasets → Melanoma landscape →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE252781_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1062441 and SRA study SRP482548. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

13 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 13 sample titles: 13 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM8007257 M397 cells,DMSO,Day0
GSM8007258 M397 cells,vemurafenib,12 hours
GSM8007259 M397 cells,vemurafenib,24 hours
GSM8007260 M397 cells,vemurafenib,36 hours
GSM8007261 M397 cells,vemurafenib,48 hours
GSM8007262 M397 cells,vemurafenib,72 hours
GSM8007263 M397 cells,vemurafenib removall,12 hours
GSM8007264 M397 cells,vemurafenib removal,24 hours
GSM8007265 M397 cells,vemurafenib removal,48 hours
GSM8007266 M397 cells,vemurafenib removal,72 hours
GSM8007267 M397 cells,vemurafenib removal,6 Days
GSM8345559 M397 cells,DMSO,72 hours
GSM8345560 M397 cells,DMSO,216 hours

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