IGF1 and cancer: CAFs are of great importance for developing drug resistance.202 CAFs-derived HGF and IGF-1 conduct primary resistance to TKIs targeting different oncogenes.203 CAFs in osimertinib-resistant NSCLC cell lines release higher IL-6, IL-8, and HGF and express more CAF markers like α-smooth muscle agonists-α (α-SMA), fibroblast activation protein (FAP), and PDGFR.204 The same scenario can be seen in patients with metastatic RCC.205 HGF can bind to MET on cancer cells to activate MEK/ERK signaling pathway.