PXD048479

PXD048479 is an original dataset announced via ProteomeXchange.

Title	Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition
Description	A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using 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 human BRAF-mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent signals, and three distinct and reversible phase transitions toward quiescence. Statistical inference of kinetically-defined regulatory modules revealed a concerted response to oncogenic BRAF inhibition and a dominant compensatory induction of SRC family kinase (SFK) signaling, which we found to be at least partially driven by accumulation of reactive oxygen species via impaired redox homeostasis. This induction sensitized cells to co-treatment with an SFK inhibitor across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the translational potential for measuring the temporal dynamics of signaling and transcriptional networks under therapeutic challenge.
HostingRepository	PRIDE
AnnounceDate	2024-02-27
AnnouncementXML	Submission_2024-02-26_16:29:12.624.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD048479
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Cameron Flower
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-11 16:18:54	ID requested
⏵ 1	2024-02-26 16:29:12	announced

10.1101/2024.02.19.581004;

10.6019/PXD048479;

submitter keyword: Melanoma, BRAF, drug resistance, phosphoproteomics, kinase inhibition

Forest M.
contact affiliation	Koch Institute for Integrative Cancer Research, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
contact email	fwhite@mit.edu
lab head
Cameron Flower
contact affiliation	Massachusetts Institute of Technology
contact email	cflower@mit.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048479
     1. Label: PRIDE project
     2. Name: Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition