Figure 3: NSCLC CAFs recurrently rescue EGFR cancers via bypass signaling.

A. PDF-secreted factors profiled by a 448-analyte multiplexed ELISA, and the gene ontology of the top 30 PDF rescue correlates (ranked by Spearman’s r). B. Effects of METi on diminishing rhHGF-driven (10ng/ml) and PDF conditioned media-driven EGFRi resistance. PDFs’ rescue against EGFRi + METi treatment (red bars) is superimposed over PDFs’ rescue against EGFRi (blue bars). Effect of each PDF conditioned medium (dots on the left and bars on the right) is tested across 12 EGFR+ cancer cells. HGF^high and HGF^low indicate PDF conditioned media with HGF level above and below the median value, respectively. Mean with 95% CI. ns, not significant; **, p < 0.01, ***, p < 0.001, ****, p < 0.0001, two-tailed t test. C. A screening across 16 compounds to identify pathway-specific inhibitors that can negate HGF/MET-independent resistance. Relative efficacy is measured by comparing cancer cells’ response to the indicated compound alone and their response to the compound in the presence of dual EGFR and MET inhibition (IC₅₀ shift). Two cancer models (MGH134 and MGH707, average is shown) are used and are tested both in the absence and presence of conditioned media from two different PDFs (HGF^high and HGF^low). D. Western blotting in two cancer cell lines showing rescue of ERK and S6 phosphorylation by PDFs and the effect of the addition of FGFRi and METi on cancer cell signaling. Bars correspond to the matched resistance effect in the presence of the indicated inhibitors. See also Figures S4-S5 and Table S2-S3.