Cabozantinib (s)-Malate

Pancreatic ductal adenocarcinoma (PDAC) remains as one of the most lethal malignancies. c-MET is an important oncogenic kinase involved in PDAC progression. We determined the anticancer effect of c-MET inhibitors, crizotinib and cabozantinib, combined with chemotherapeutic agents, doxorubicin, oxaliplatin and gemcitabine, against different PDAC and a lung adenocarcinoma cell line expressing different levels of c-MET. MTT assay was performed to assess cell growth inhibition. Synergistic combinations were evaluated in spheroid cultures, while apoptosis was determined through Hoechst33258 staining. The effect of drug combinations on cell cycle and apoptosis induction was examined by RNase/PI flow cytometric assay. We also evaluated reactive oxygen species (ROS) levels using 2',7'-dichlorofluorescein-diacetate (DCFH-DA) assay to explore the possible mechanisms contributing to synergism. Combination of crizotinib or cabozantinib with doxorubicin exhibited synergistic effects in c-MET overexpressing cells. Conversely, combinations of c-MET inhibitors with other agents were additive or even antagonistic. Combination index (CI) values calculated with Calcusyn software were 0.631-0.730 for crizotinib and 0.542-0.746 for cabozantinib co-administered with doxorubicin. These synergistic combinations showed significant spheroid growth inhibition and apoptosis induction in Suit-2, c-MET dependent PDAC cells. These combinations also significantly increased the number of cells in both apoptotic sub-G1 phase and the G2/M phase compared to single-drug treatment. Increased ROS production seemed to be a possible mechanism underlying synergism. In conclusion, c-MET inhibitors synergize with DNA damaging agent, doxorubicin, in cancer cells with c-MET overexpression, indicating that these combination therapies may be a promising cancer therapeutic strategy.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARβ interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARβ complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARβ complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.