PXD027877-1

PXD027877 is an original dataset announced via ProteomeXchange.

Title	Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade
Description	KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. Here, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. This interaction targets KRAS-directed oncogenic signaling in the aggressive and therapy resistant non-glandular mesenchymal subtype of PDAC, driven by an allelic imbalance, increased gene-dosage and expression of oncogenic KRAS. Mechanistically, the combinatorial treatment induces cell cycle arrest and cell death and initiates an interferon response. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition. This work opens new avenues to target the therapy refractory mesenchymal PDAC subtype.
HostingRepository	PRIDE
AnnounceDate	2022-02-11
AnnouncementXML	Submission_2022-02-11_06:56:39.959.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-08-11 22:18:54	ID requested
⏵ 1	2022-02-11 06:56:40	announced

Falcomat, à C, B, ä, rthel S, Widholz SA, Schneeweis C, Montero JJ, Toska A, Mir J, Kaltenbacher T, Heetmeyer J, Swietlik JJ, Cheng JY, Teodorescu B, Reichert O, Schmitt C, Grabichler K, Coluccio A, Boniolo F, Veltkamp C, Zukowska M, Vargas AA, Paik WH, Jesinghaus M, Steiger K, Maresch R, Ö, llinger R, Ammon T, Baranov O, Robles MS, Rechenberger J, Kuster B, Meissner F, Reichert M, Flossdorf M, Rad R, Schmidt-Supprian M, Schneider G, Saur D, Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Nat Cancer, 3(3):318-336(2022) [pubmed]

submitter keyword: Mass spectrometry, proteomics, pancreatic cancer, combination therapy, immune checkpoint inhibition

Felix Meißner
contact affiliation	University of Bonn, Institute of Innate of Innate Immunity, department for systems immunology & proteomics
contact email	felix.meissner@ukbonn.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD027877

PRIDE project URI

• PRIDE
  1. PXD027877
     1. Label: PRIDE project
     2. Name: Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade