Hepatocyte growth factor receptor and Tubulin (MET/Tubulin)

The MET (Hepatocyte Growth Factor Receptor) and Tubulin dual target represents a synergistic therapeutic strategy in oncology, combining the inhibition of a key oncogenic signaling pathway with the disruption of the cellular structural machinery required for division [1, 10]. MET is a receptor tyrosine kinase that, upon activation by its ligand Hepatocyte Growth Factor (HGF), triggers intracellular pathways involved in cell survival, proliferation, and metastasis [15]. Tubulin is the fundamental building block of microtubules, which are essential for mitotic spindle formation and intracellular transport [19]. Drugs targeting this combination, most notably tivantinib (ARQ 197), aim to overcome the limitations of single-agent therapies and bypass resistance mechanisms [2, 4]. While tivantinib was initially characterized as a selective MET inhibitor, subsequent research revealed its potent activity as a tubulin depolymerizer, binding to the colchicine site and inducing G2/M cell cycle arrest [5, 6]. This dual mechanism is particularly relevant in cancers like hepatocellular carcinoma and non-small cell lung cancer, where MET signaling is often dysregulated and microtubule dynamics are critical for rapid tumor growth [7, 12]. However, clinical trials have faced challenges, including dose-limiting toxicities such as neutropenia and the failure of some phase III studies to meet primary endpoints [1, 15].

Other names

c-MET and TubulinHGFR and TubulinMET + TubulinMET/Tubulin dual target

Dual inhibition of the MET receptor tyrosine kinase and microtubule polymerization. Drugs like tivantinib bind to the colchicine binding site of tubulin to induce depolymerization while also potentially inhibiting MET signaling, leading to G2/M phase cell cycle arrest and apoptosis.