Synergistic inhibition of tumor growth by MET and COX-2 targeting in gastric and colorectal cancers.

Gastric and colorectal cancers are common and deadly across the globe. Preclinical findings propose that the pairing of MET inhibitors with anti-inflammatory drugs could synergistically impede tumor growth and reshape the tumor microenvironment. This study introduces AspMet, a novel dual-targeting inhibitor of c-Met and COX-2. In vitro experiments demonstrated that AspMet significantly inhibited the proliferation of MKN45 (IC50 = 1.05 ± 0.02 nM) and SW480 (IC50 = 1.32 ± 0.01 μM) cell lines. The experimental data indicate that AspMet effectively blocks several cancer-promoting signaling pathways, including c-Met、TRKB、COX-2 and HIF-1α, significantly inhibits epithelial-mesenchymal transition, thus decreasing tumor cell migration and invasion, and causes DNA damage, resulting in G0/G1 cell cycle arrest and the initiation of apoptosis. Furthermore, AspMet has strong anti-angiogenic properties. In animal models, AspMet significantly reduced the growth of subcutaneous tumors in both gastric and colorectal cancers，and it has an extremely high bioavailability. Therefore, the dual inhibition strategy targeting c-Met and COX-2 offers a promising novel approach for the treatment of cancers, particularly inflammatory cancers.