PXD053444

PXD053444 is an original dataset announced via ProteomeXchange.

Title	Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling
Description	Cancer-associated fibroblasts (CAFs) are associated with tumor progression and modulate drug sensitivity of cancer cells. However, the underlying mechanisms are often incompletely understood and crosstalk between tumor cells and CAFs can involve soluble secreted as well as adhesion proteins . Interrogating a panel of non-small cell lung cancer (NSCLC) cell lines driven by EML4-ALK fusions we observed substantial CAF-mediated drug resistance to various clinical ALK tyrosine kinase inhibitors (TKIs). Array-based cytokine and kinome profiling of fibroblast-derived conditioned-media identified HGF-MET signaling as a major contributor to CAF-mediated paracrine resistance that can be overcome by MET TKIs. However, ‘Cell Type specific labeling using Amino acid Precursors’ (CTAP)-based expression and phosphoproteomics in direct coculture also highlighted a critical role for the fibronectin-integrin pathway. Flow cytometry analysis confirmed activation of integrin 1 (ITGB1) in lung cancer cells by CAF coculture. Treatment with pharmacological inhibitors, cancer cell-specific silencing or CRISPR-Cas9-mediated knockout of ITGB1 overcame adhesion protein-mediated resistance. Concurrent targeting of MET and integrin signaling effectively abrogated CAF-mediated resistance of EML4-ALK-driven NSCLC cells to ALK TKIs in vitro. Consistently, combination of the ALK TKI, alectinib, with the MET TKI, capmatinib, and/or the integrin inhibitor, cilengitide, was significantly more efficacious than single agent therapy in suppressing tumor growth using an in vivo EML4-ALK-dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can lead to more effective therapeutic approaches.
HostingRepository	PRIDE
AnnounceDate	2025-12-11
AnnouncementXML	Submission_2025-12-11_08:36:20.674.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD053444
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-26 19:10:11	ID requested
⏵ 1	2025-12-11 08:36:21	announced

10.6019/PXD053444;

submitter keyword: Phosphoproteomics,Lung Cancer, Coculture, Expression Proteomics, ALK

Uwe Rix
contact affiliation	Drug Discovery Moffitt Cancer Center Tampa, FL, USA
contact email	uwe.rix@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053444
     1. Label: PRIDE project
     2. Name: Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling