Research Paper Volume 13, Issue 5 pp 6890—6903

MET inhibitor, capmatinib overcomes osimertinib resistance via suppression of MET/Akt/snail signaling in non-small cell lung cancer and decreased generation of cancer-associated fibroblasts

Osimertinib-resistant cells promoted CAF transformation. (A) Expression profile analysis of TCGA lung cancer cohorts showed that an elevated MET mRNA level in both lung adenocarcinoma and squamous cell lung cancer tissues as compared to the normal lung tissue. *PB) Western blots analysis showed that osimertinib resistant (OR) NSCLC samples contained a higher EGFR, Akt and MET activities (p-, phosphorylated form) and higher expression of EMT markers, vimentin and snail, than osimertinib sensitive (OS) counterparts. (C) ELISA assay of medium collected from OR and OS cells showed that OR cells produced a significantly higher amount of TGFβ1 as compared to OS cells. (D) Immunofluorescence examination of fibroblasts after co-cultured with OR or OS cells. Fibroblasts co-cultured with OR cells showed a markedly stronger fluorescence intensity of both CAF makers, α-SMA (green) and vimentin (red), comparing to fibroblasts co-cultured with OS cells (magnification 200X).

Figure 2. Osimertinib-resistant cells promoted CAF transformation. (A) Expression profile analysis of TCGA lung cancer cohorts showed that an elevated MET mRNA level in both lung adenocarcinoma and squamous cell lung cancer tissues as compared to the normal lung tissue. *P<0.05. (B) Western blots analysis showed that osimertinib resistant (OR) NSCLC samples contained a higher EGFR, Akt and MET activities (p-, phosphorylated form) and higher expression of EMT markers, vimentin and snail, than osimertinib sensitive (OS) counterparts. (C) ELISA assay of medium collected from OR and OS cells showed that OR cells produced a significantly higher amount of TGFβ1 as compared to OS cells. (D) Immunofluorescence examination of fibroblasts after co-cultured with OR or OS cells. Fibroblasts co-cultured with OR cells showed a markedly stronger fluorescence intensity of both CAF makers, α-SMA (green) and vimentin (red), comparing to fibroblasts co-cultured with OS cells (magnification 200X).