Antitumor activities of BIBF 1120, BI 860585, and BI 836845 in preclinical models of sarcoma

Sarcomas are rare mesenchymal malignancies with diverse clinical and pathological features. Although the use of adjuvant chemotherapy for sarcomas leads to remarkable clinical benefits, novel anticancer drugs are required for better clinical outcomes in patients with sarcomas. Aberrant regulation of many tyrosine kinases drives the defective signaling pathways in sarcomas. We examined the inhibitory effects of three drugs on signal transduction pathways in sarcomas, using a panel of 20 sarcoma cell lines with different histological origins. The effects of BIBF 1120 on the triple receptor kinase pathway, BI 860585 on the mTOR signaling pathway, and BI 836845 on the insulin-like growth factor (IGF)-induced signal transduction pathway were investigated. Osteosarcoma, rhabdomyosarcoma, synovial sarcoma, and Ewing sarcoma cell lines were used for the study. Our findings indicated that BIBF 1120 may preferentially inhibit the viability of synovial sarcoma cell lines, BI 860585 may have inhibitory effects on the viability of sarcoma cells with different histological features, BI 836845 may have specific inhibitory effects in Ewing sarcoma, and IGF-1 receptor may be a predictive biomarker of sarcomas. However, further investigations on the molecular mechanisms involved in the responses to treatments with the three inhibitors are necessary for developing novel therapeutic strategies against sarcomas. Introduction Sarcomas are mesenchymal malignancies with different histological backgrounds. The clinical features of sarcomas range from curable to metastatic tumors, which result in short-term survival. Although surgical resection is the treatment of choice for the localized disease, 50% of high-grade sarcomas tend to recur [1]. The use of adjuvant chemotherapy, which started in the early 1970s, led to remarkable improvements in the outcome of sarcoma patients. For example, the survival rates of patients with localized osteosarcoma [2-6] and Ewing sarcoma [7-9], both of which are sensitive to chemotherapy, were improved from approximately 20% to 70% by adding multiagent chemotherapy to the surgical removal of the tumors. However, intensified chemotherapy has not been noted to substantially improve the clinical outcomes of osteosarcoma [10,11] or Ewing sarcoma [12,13]. Moreover, in sarcomas that do not respond well to chemotherapy, the role of adjuvant treatment remains a subject of discussion because its potential benefit does not exceed its side effects. These notions drove the development of a novel therapeutic strategy such as targeted one [14]. The advent of targeted drugs has considerably contributed to the recent trends in sarcoma treatment [15]. The US Food and Drug Administration (FDA) has approved the following targeted drugs for the treatment of soft tissue sarcomas: imatinib mesylate [16], pazopanib hydrochloride [17], eribulin mesylate [18], and trabectedin [19]. Immunotherapeutic approaches have also been introduced for the treatment of sarcomas [20]. Considering the substantial number of FDA-approved targeted drugs for treating other malignancies, a higher number of targeted drugs will be adapted to sarcoma treatments. In this study, we examined the inhibitory effects of three drugs: BIBF 1120 (nintedanib), BI 860585, and BI 836845, on signal transduction pathways. BIBF 1120 is a triple kinase inhibitor, which blocks the receptor pathway of vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor [21,22]. BIBF 1120 inhibits members of the kinase family of proteins such as Src, Lck, and Lyn. In addition to the receptor-mediated signal pathways in the cells, BIBF 1120 also targets the interaction between cancer cells and the tumor microenvironment in lung cancer [23]. A phase I study suggested that BIBF 1120 has antitumor activity against many types of cancers such as colorectal cancer, renal cancer, and hepatocellular carcinoma [24]. The usefulness of BIBF 1120 as an anticancer agent against non-small cell lung cancer has been proved in preclinical and clinical phase I and II trials [25]. A phase II clinical trial on the efficacy of BIBF 1120 in metastatic soft tissue sarcomas (NCT02808247) has been recently launched. BI 860585 is an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and a downstream effector of the PI3K/AKT pathway [26]. mTORC1 and mTORC2 are complexes formed from mTOR. mTORC1 is sensitive to rapamycin and is involved in mRNA translation, whereas mTORC2 is resistant to rapamycin and regulates actin cytoskeleton. Aberrant regulations of mTORC1 and mTORC2 have been reported in many cancers. Rapamycin and its Correspondence to: Tadashi Kondo, Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045, Japan, Tel: +81 3 3542 2511 (ex 3003); Fax: +81 3 3547 5298; E-mail: takondo@ncc.go. jp