Fang, Zhenghuan Han, Boreum Jung, Kyung Hee Lee, Ju-Hyeon El-Damasy, Ashraf Kareem Gadhe, Changdev G. Kim, Soo Jung Yan, Hong Hua Park, Jung Hee Lee, Ji Eun Kang, Yeo Wool Pae, Ae Nim Keum, Gyochang Hong, Soon-Sun 2024-01-19T22:31:36Z 2024-01-19T22:31:36Z 2021-09-03 2018-07 0304-3835 https://pubs.kist.re.kr/handle/201004/121228 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. (C) 2018 Elsevier B.V. All rights reserved. English ELSEVIER IRELAND LTD BREAST-CANCER DUCTAL ADENOCARCINOMA TRK INHIBITOR CELLS GROWTH RECEPTORS APOPTOSIS GEMCITABINE METASTASIS EXPRESSION A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer Article 10.1016/j.canlet.2018.03.041 1 CANCER LETTERS, v.426, pp.25 - 36 CANCER LETTERS 426 25 36 scie scopus 000432877900004 2-s2.0-85045430991 Oncology Oncology Article BREAST-CANCER DUCTAL ADENOCARCINOMA TRK INHIBITOR CELLS GROWTH RECEPTORS APOPTOSIS GEMCITABINE METASTASIS EXPRESSION Tropomyosin-related kinase A (TrkA) KK5101 Pancreatic cancer Apoptosis