Paradoxical drug sensitization of lung cancer cells by stromal fibroblast-secreted IGF-binding proteins: Phosphotyrosine Profiling

ABSTRACT: Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment often linked to drug resistance. Here, we report that CAFs, but not normal fibroblasts, can promote either resistance or unexpected drug sensitization of different lung cancer cells. Using unbiased secretomics, transcriptomics and tyrosine phosphoproteomics, we observed differential expression of several IGF1R signaling components, such as IGF-binding proteins and IGF1/2, and downstream signaling effects on cancer cells by fibroblasts. IGF1/2 treatment or IGFBP5 silencing in CAFs reversed, while addition of exogenous IGFBPs or pharmacological IGF1R inhibitors phenocopied the sensitizing effects. Combining IGF1R and EGFR inhibitors synergized in 2D and 3D models of different drug-resistant and naïve EGFR-mutant lung cancer cells and decreased tumor growth in vivo. These results suggest that multiple resistance mechanisms coexist within the same cancer cells, that CAFs context-dependently cause drug resistance or sensitization, and that understanding both of these differential mechanisms leads to improved therapeutic approaches.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung Epithelium

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: John Koomen  

LAB HEAD: Uwe Rix, PhD

PROVIDER: PXD023692 | Pride | 2023-03-11

REPOSITORIES: Pride