Dataset Information

Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Type Ii Pneumocyte, Fibroblast

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: John Koomen

LAB HEAD: Uwe Rix

PROVIDER: PXD053444 | Pride | 2025-12-11

REPOSITORIES: Pride

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			Action	DRS
	20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx01.raw	Raw
	20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx01.raw__F003769_.dta	Raw
	20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx01.raw__F003769_.mzid.gz	Mzid
	20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx01.raw__F003769_.mzid_20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx01.raw__F003769_.MGF	Mzid
	20210203_Qianqian_Rix_CTAP_TMTpro16_Expression_Fx02.raw	Raw

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Dataset Information

Cancer-associated fibroblasts confer ALK inhibitor resistance in EML4-ALK-driven lung cancer via concurrent integrin and MET signaling

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