A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer
- A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer
- 배애님; 금교창; 가디 장데부 고라크스나트; 이주현; 아쉬라프 카림; Zhenghuan Fang; 한보름; 정경희; 김수정; Hong Hua Yan; 박정희; 이지은; 강여울; 홍순선
- Tropomyosin-related kinase A (TrkA); KK5101; Pancreatic cancer; Apoptosis
- Issue Date
- Cancer letters
- VOL 426-36
- Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay. It effectively inhibited the growth and proliferation of pancreatic cancer cells. Also, KK5101 increased apoptosis with loss of mitochondrial membrane potential, as evidenced by increases of cytochrome c releases. It increased numbers of TUNEL-positive apoptotic cells, and cell death including early and late apoptosis by Annexin V assay. In addition, activation of the TrkA signaling cascades including p-AKT, p-MEK, and p-STAT3 were inhibited by KK5101 treatment in vitro, as well as ex vivo tumor spheroid models, resulting in potent induction of apoptosis. Importantly, KK5101 also significantly attenuated tumor growth of in vivo pancreatic cancer models. These findings indicate that KK5101 may exert antitumor effects by directly affecting cancer cell growth or survival via inhibition of TrkA signaling pathway. We therefore suggest that KK5101 is a novel therapeutic candidate for treating pancreatic cancer.
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