Tivantinib Research Articles

Comparison of autophagy inducibility in various tyrosine kinase inhibitors and their enhanced cytotoxicity via inhibition of autophagy in cancer cells in combined treatment with azithromycin

Tyrosine kinase inhibitors (TKIs) induce autophagy in many types of cancer cells. We previously reported that gefitinib (GEF) and imatinib (IMA) induce autophagy in epidermal growth factor receptor (EGFR) knock-out A549 and non-BCR-ABL-expressing leukemia cell lines, respectively. This evidence suggests that TKI-induced autophagy is independent of the original target molecules. The present study compared the autophagy-inducing abilities of various TKIs, regardless of their targets, by quantitative autophagy flux assay. We established stable clones expressing the GFP-LC3-mCherry-LC3ΔG plasmid in A549, PC-9, and CAL 27 cell lines and assessed autophagy inducibility by monitoring the fluorescent ratios of GFP-LC3 to mCherry-LC3ΔG using an IncuCyte live cell imaging system during exposure to TKIs viz; GEF, osimertinib (OSI), lapatinib (LAP), lenvatinib (LEN), sorafenib (SOR), IMA, dasatinib (DAS), and tivantinib (TIV). Among these TKIs, DAS, GEF, and SOR exhibited prominent autophagy induction in A549 and PC-9 cells. In CAL 27 cells, IMA, SOR, and LEN, but not GEF, TIV, or OSI, exhibited autophagy induction. In the presence of azithromycin (AZM), which showed an inhibitory effect on autophagy flux, TKIs with prominent autophagy inducibility exhibited enhanced cytotoxicity via non-apoptotic cell death relative to effects of TKI alone. Therefore, autophagy inducibility of TKIs differed in the context of cancer cells. However, once induced, they appeared to have cytoprotective functions. Thus, blocking TKI-induced autophagy with AZM may improve the therapeutic effect of TKIs in cancer cells.

Research hotspots and updates of diagnosis and treatment of hepatocellular carcinoma from 2017 annual meeting of the American Society of Clinical Oncology

There were many progressions of hepatoce-llular carcinoma (HCC) in the 2017 annual meeting of the American Society of Clinical Oncology (ASCO). (1) Sorafenib has been at the heart of treatment for advanced HCC, meanwhile, it has been confirmed to effectively prolong the life time of patients and improve the clinical efficacies combined with other therapies. A variety of molecular and clinical indicators also help screening out peoples. (2) New molecular targeted drugs have sprung up, and Lenvatinib (multiple receptor tyrosine kinases inhibitor) is expected to become the next first-line drug. The second-line Regorafenib has obtained supporting evidence from evidence-based medicine, and a combination therapy of Sorafenib and Regorafenib promises to be a new model of targeted therapy for HCC. However, the phase Ⅲ study (METIV-HCC) of which Tivatinib (ARQ 197) becomes the second-line drug for HCC has failed. (3) Immunization therapy remains a hotspot for HCC. The monoclonal antibodies of immunological checkpoint and adoptive immunotherapy have better safety and clinical efficacy. (4) Primary lesions resection of HCC and drug control of metastatic lesions are expected to be the therapy model for metastatic HCC. The liver transplantation for primary HCC will be further developed. (5) The combination and sequential application of multiple therapies will become an inevitable choice, and efficacy of stereotactic body radiation therapy is expected. The combination and sequential application of transcatheter arterial chemoembolization (TACE) and other therapies is still a main therapy for unresectable HCC. (6) The new predictors and models of pro-gnosis have been popping up, nevertheless, its therapy effects should be further proven. Key words: Hepatic neoplasms; Sorafenib; Targeted therapy; Immunologic therapy

MET-inhibitors meet MET mutations in lung cancer

Mesenchymal-to-epithelial transition ( MET ) exon 14 mutation in non-small cell lung cancer (NSCLC) has been recognized. However, clinical, molecular, and pathologic features have not been well understood. Awad et al . described NSCLC patients with MET exon 14 mutations precisely in the ‘ Journal of Clinical Oncology 2016;34:721-30’. Among 933 non-squamous NSCLC patients, they found 28 (3.0%) patients who represented a unique clinical and molecular subtype of NSCLC. Median age of the 28 patients was 72.5 years, 68% were women, 36% were never-smokers, 64% had stage IV, 100% were white, non-Hispanic, and 64% had adenocarcinoma and 14% had pleomorphic carcinoma. Genomic deletions and point mutations occurred in 17 and 11, respectively, occurred of the 28 patients. Although none of the 28 patients with MET exon 14 mutations had KRAS , epidermal growth factor receptor ( EGFR ), ERBB2 , anaplastic lymphoma kinase ( ALK ), ROS1 , or RET alterations, mutations of TP53 , CDKN2A/B , BRAF600E , PIK3CA , PTEN , RB1 , ATM , BRCA2 , NF1 , or ARID2 were co-existed. Amplification of MDM2 was observed in 13 (46%), and 6 (21%) and 8 (29%) had high- and low-level MET copy gain, respectively. To date, two MET inhibitors, onartuzumab or tivantinib, combination with erlotinib in previously treated NSCLC were investigated in phase III trials. However, neither showed prolonged overall survival (OS) compared with erlotinib alone in molecularly unselected patients. Several publications including the report of Awad et al . revealed that patients with MET exon 14 mutation were successfully treated with MET-tyrosine kinase inhibitors (TKIs) such as crizotinib. Prospective trials using MET-TKIs in MET exon 14 mutated NSCLC are ongoing. Concerning translational research, significance of co-existed other mutations or amplifications and mechanism of acquired resistance to MET-TKIs remain to be clarified. Finally, the therapeutic strategies against the MET-TKI resistance and intracranial metastasis in NSCLC with MET exon 14 mutation should be elucidated.

Radiosensitizing effect of ARQ197, a small-molecule tyrosine kinase inhibitor of c-Met, on lung cancer cell line H1299

Objective To evaluate the radiosensitizing effect and action mechanism of a tyrosine kinase inhibitor, ARQ197, on lung cancer cell line H1299. Methods H1299 cells were treated with different concentrations of recombinant human hepatocyte growth factor (HGF) and ARQ197, respectively. Colony formation assay was used to investigate the proliferation of H1299 cells, and the optimal concentrations of HGF and ARQ197 were figured out for the radiosensitivity study. H1299 cells were divided into control, HGF-treated, ARQ197-treated, and HGF+ ARQ197-treated groups, and the differences between those groups were evaluated. The impacts of HGF, radiation alone, or HGF+ ARQ197 on the expression and activation of c-Met and the downstream Akt and Erk1/2 were determined by Western blot. Results The colony formation rate of H1299 cells increased with increasing HGF concentration, and decreased with increasing ARQ197 concentration. Using the linear-quadratic model, the cell survival curve showed that the radiation dose enhancement ratios for H1299 cells treated with HGF, HGF+ ARQ197, and ARQ197 were 0.85, 1.20, and 1.27, respectively, when the surviving fraction was 0.1. The expression of pc-Met, p-Akt, and p-Erk1/2 proteins increased in H1299 cells after HGF stimulation. In HGF+ ARQ197-treated cells, the expression of pc-Met, p-Akt, and p-Erk1/2 proteins decreased with increasing ARQ197 concentration. After 2 Gy irradiation, the expression of pc-Met, p-Akt, and p-Erk1/2 proteins increased in HGF-treated cells but substantially decreased in HGF+ ARQ197-treated cells, while there were no significant changes in the expression of total c-Met, Akt, and Erk1/2 proteins. Conclusions ARQ197 has a substantial radiosensitizing effect on lung cancer cell line H1299 in vitro by inhibiting HGF/c-Met and activation of downstream signaling pathways. Key words: H1299 cell line; Radiosensitivity; c-Met tyrosine kinase inhibitor

Extended Progression-Free Survival in Two Patients With Alveolar Soft Part Sarcoma Exposed to Tivantinib

Extended Progression-Free Survival in Two Patients With Alveolar Soft Part Sarcoma Exposed to Tivantinib