A novel anti-c-Kit antibody-drug conjugate to treat wild-type and activating-mutant c-Kit-positive tumors.
Jin-Ock KimKwang-Hyeok KimEun Ji BaekBomi ParkMin Kyung SoByoung Joon KoHan-Jik KoSang-Gyu ParkPublished in: Molecular oncology (2021)
c-Kit overexpression and activating mutations, which are reported in various cancers, including gastrointestinal stromal tumor (GIST), small-cell lung cancer (SCLC), acute myeloid leukemia, acral melanoma, and systemic mastocytosis (SM), confer resistance to tyrosine kinase inhibitors (TKIs). To overcome TKI resistance, an anti-c-Kit antibody-drug conjugate was developed in this study to treat wild-type and mutant c-Kit-positive cancers. NN2101, a fully human IgG1, was conjugated to DM1, a microtubule inhibitor, through N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) (to give NN2101-DM1). The antitumor activity of NN2101-DM1 was evaluated in vitro and in vivo using various cancer cell lines. NN2101-DM1 exhibited potent growth-inhibitory activities against c-Kit-positive cancer cell lines. In a mouse xenograft model, NN2101-DM1 exhibited potent growth-inhibitory activities against imatinib-resistant GIST and SM cells. In addition, NN2101-DM1 exhibited a significantly higher anti-cancer effect than carboplatin/etoposide against SCLC cells where c-Kit does not mediate cancer pathogenesis. Furthermore, the combination of NN2101-DM1 with imatinib in imatinib-sensitive GIST cells induced complete remission compared with treatment with NN2101-DM1 or imatinib alone in mouse xenograft models. These results suggest that NN2101-DM1 is a potential therapeutic agent for wild-type and mutant c-Kit-positive cancers.
Keyphrases
- wild type
- induced apoptosis
- chronic myeloid leukemia
- small cell lung cancer
- glycemic control
- papillary thyroid
- acute myeloid leukemia
- cell cycle arrest
- signaling pathway
- squamous cell
- childhood cancer
- rheumatoid arthritis
- squamous cell carcinoma
- oxidative stress
- acute lymphoblastic leukemia
- cancer therapy
- radiation therapy
- anti inflammatory
- cell proliferation
- metabolic syndrome
- transcription factor
- young adults
- epidermal growth factor receptor
- advanced non small cell lung cancer
- tyrosine kinase
- weight loss
- ulcerative colitis
- combination therapy
- allogeneic hematopoietic stem cell transplantation