Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma

Abstract

Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10–18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma.

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

“…In the present study, we report the potential interactions of sitravatinib with ABCB1 and ABCG2 in human multidrug-resistant cancer cells. First, the determined cytotoxicity of sitravatinib in our drug-sensitive and multidrug-resistant cell lines is comparable to the cytotoxic profile of sitravatinib reported by others in previous studies [25,53,54]. In contrast to imatinib [32] and dasatinib [34], we found that cells overexpressing ABCB1 or ABCG2 were not resistant to sitravatinib (Figure 1).…”

“…Sitravatinib is an orally bioavailable TKI that targets multiple receptor tyrosine kinases [25] and potentiates immune checkpoint blockade to help cancer patients that are resistant to immune therapy [53]. In the present study, we report the potential interactions of sitravatinib with ABCB1 and ABCG2 in human multidrug-resistant cancer cells.…”

“…As an alternative, we and others have been investigating the potential repurposing of tyrosine kinase inhibitors (TKIs) as modulators of ABCB1 and ABCG2 to resensitize multidrug-resistant cancer cells to chemotherapeutic agents [18][19][20][21][22][23][24]. Sitravatinib (MGCD516) is a promising new receptor tyrosine kinase inhibitor [25] that is currently being evaluated in clinical trials for patients with MBC (ClinicalTrials.gov Identifier: NCT04123704), squamous cell carcinoma (SCC) (NCT03575598), advanced liposarcoma (NCT02978859), advanced urothelial carcinoma (NCT03606174), advanced clear cell renal cell carcinoma (NCT03680521), non-small cell lung cancer (NSCLC) (NCT02664935), advanced non-squamous NSCLC (NCT03906071), advanced solid tumour malignancies (NCT02219711 and NCT03666143), advanced kidney cancer (NCT03015740) and unresectable locally advanced hepatocellular carcinoma (HCC) or gastric/gastroesophageal junction cancer (GC/GEJC) (NCT03941873). At this time, the relationship between sitravatinib and ABCB1 or ABCG2 remains elusive.…”

Sitravatinib potentiates immune checkpoint blockade in refractory cancer models

“…In 3 different preclinical tumor models, including KLN205, an aggressive lung cancer model that is resistant to checkpoint blockade, the tumor response to sitravatinib and glesatinib was rapid and consistent ( Figure 2, A-C, and Supplemental Figure 2, A-C). Consistently, sitravatinib was also found to have potent antitumor activity in preclinical models of sarcoma (17). RNA was isolated from KLN205 tumors treated for 6 days with sitravatinib (sitra) or glesatinib (gles) and was analyzed using a preassembled nCounter PanCancer Immune Profiling Panel (mouse) and the nCounter system (NanoString Technologies).…”

Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application

“…Similar to entrectinib, the clinical success of sitravatinib will rest on the ability to appropriately enrich patients for targetable, molecular lesions. Although blockade of multiple driver signaling pathways can be achieved with sitravatinib, 190…”