PXD023267-1

PXD023267 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	2022-02-23
AnnouncementXML	Submission_2022-02-23_06:21:40.302.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Julia Rechenberger
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-22 02:13:35	ID requested
⏵ 1	2022-02-23 06:21:40	announced
2	2023-11-14 08:52:01	announced	2023-11-14: Updated project metadata.

10.1038/S43018-021-00326-1;

submitter keyword: pancreatic cancer, combination therapy, immune checkpoint inhibition, scRNA-seq, LC-MS/MS, Kinobead Pull-Downs

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics Technical University of Munich Partner Site of the German Cancer Consortium
contact email	kuster@tum.de
lab head
Julia Rechenberger
contact affiliation	Chair of Proteomics and Bioanlytics, Technical University of Munich
contact email	julia.rechenberger@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023267
     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