IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells.

Autor: Remsing Rix LL; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA., Sumi NJ; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Hu Q; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Desai B; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Bryant AT; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA., Li X; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA., Welsh EA; Biostatistics and Bioinformatics Shared Resource, Moffitt Cancer Center, Tampa, FL 33612, USA., Fang B; Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Kinose F; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Kuenzi BM; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Chen YA; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA.; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA., Antonia SJ; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Lovly CM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Koomen JM; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.; Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA., Haura EB; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Marusyk A; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.; Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL 33612, USA., Rix U; Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2022 Aug 16; Vol. 15 (747), pp. eabj5879. Date of Electronic Publication: 2022 Aug 16.
DOI: 10.1126/scisignal.abj5879
Abstrakt: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are often linked to drug resistance. Here, we found that coculture with CAFs or culture in CAF-conditioned medium unexpectedly induced drug sensitivity in certain lung cancer cell lines. Gene expression and secretome analyses of CAFs and normal lung-associated fibroblasts (NAFs) revealed differential abundance of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs), which promoted or inhibited, respectively, signaling by the receptor IGF1R and the kinase FAK. Similar drug sensitization was seen in gefitinib-resistant, EGFR -mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which IGFBP5 or IGFBP6 was silenced. Phosphoproteomics and receptor tyrosine kinase (RTK) array analyses indicated that exposure of PC9GR cells to CAF-conditioned medium also inhibited compensatory IGF1R and FAK signaling induced by the EGFR inhibitor osimertinib. Combined small-molecule inhibition of IGF1R and FAK phenocopied the CAF-mediated effects in culture and increased the antitumor effect of osimertinib in mice. Cells that were osimertinib resistant and had MET amplification or showed epithelial-to-mesenchymal transition also displayed residual sensitivity to IGFBPs. Thus, CAFs promote or reduce drug resistance in a context-dependent manner, and deciphering the relationship between the differential content of CAF secretomes and the signaling dependencies of the tumor may reveal effective combination treatment strategies.
Databáze: MEDLINE
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