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

Combination treatment of capmatinib and osimertinib overcame osimertinib resistance and improved survival in PDX mouse model. (A) Tumor burden over time curve shows that the combination treatment (Cap+Osi) group with the lowest tumor burden followed by capmatinib only (cap) group while no difference between the control and osimertinib (osi) only groups. (B) Survival ratio versus time curve indicates that the best survival rate in the following order, combination treatment (cap+osi), capmatinib (cap) only, and lowest in both control and osimertinib (osi) only groups. (C) Immunohistochemical analysis of tumor samples. The lowest staining intensity of Snail MET and α-SMA was found in the combination group followed by the capmatinib only samples while the immunostaining of all three markers were highest in the control and osimertinib only tumor sections. (D) Comparative tumor formation assay shows that the lowest number of tumor spheres were formed in the samples which received the combination treatment followed by capmatinib only. Tumor samples from control and osimertinib only groups showed similar tumor forming ability. (E) ELISA assay of secreted TGFβ1 secretion by the tumor samples with different treatment regimens. The lowest amount of TGFβ1 secreted into the medium was observed in the tumor samples received combination treatment. **P

Figure 5. Combination treatment of capmatinib and osimertinib overcame osimertinib resistance and improved survival in PDX mouse model. (A) Tumor burden over time curve shows that the combination treatment (Cap+Osi) group with the lowest tumor burden followed by capmatinib only (cap) group while no difference between the control and osimertinib (osi) only groups. (B) Survival ratio versus time curve indicates that the best survival rate in the following order, combination treatment (cap+osi), capmatinib (cap) only, and lowest in both control and osimertinib (osi) only groups. (C) Immunohistochemical analysis of tumor samples. The lowest staining intensity of Snail MET and α-SMA was found in the combination group followed by the capmatinib only samples while the immunostaining of all three markers were highest in the control and osimertinib only tumor sections. (D) Comparative tumor formation assay shows that the lowest number of tumor spheres were formed in the samples which received the combination treatment followed by capmatinib only. Tumor samples from control and osimertinib only groups showed similar tumor forming ability. (E) ELISA assay of secreted TGFβ1 secretion by the tumor samples with different treatment regimens. The lowest amount of TGFβ1 secreted into the medium was observed in the tumor samples received combination treatment. **P<0.01, ***P<0.001, NS, no significance.