Biomolecules & Therapeutics

  • 제30권4호
  • /
  • Pages.360-367
  • /
  • 2022
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects

  • Lee, Hyo Jeong (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University) ;
  • Moon, Yeongyu (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Choi, Jungil (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Heo, Jeong Doo (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Kim, Sekwang (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University) ;
  • Nallapaneni, Hari Krishna (College of Pharmacy, Kangwon National University) ;
  • Chin, Young-Won (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Lee, Jongkook (College of Pharmacy, Kangwon National University) ;
  • Han, Sun-Young (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
  • 투고 : 2021.12.28
  • 심사 : 2022.02.09
  • 발행 : 2022.07.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

키워드

과제정보

This research was funded by the National Research Foundation, Government of Korea, grant number 2021R1A2C1007790 (S-Y.H.) and 2021R1A2C2010431 (J.L.).

참고문헌

  1. Al-Salama, Z. T. and Keam, S. J. (2019) Entrectinib: first global approval. Drugs 79, 1477-1483. https://doi.org/10.1007/s40265-019-01177-y
  2. Ardini, E., Bosotti, R., Borgia, A. L., De Ponti, C., Somaschini, A., Cammarota, R., Amboldi, N., Raddrizzani, L., Milani, A., Magnaghi, P., Ballinari, D., Casero, D., Gasparri, F., Banfi, P., Avanzi, N., Saccardo, M. B., Alzani, R., Bandiera, T., Felder, E., Donati, D., Pesenti, E., Sartore-Bianchi, A., Gambacorta, M., Pierotti, M. A., Siena, S., Veronese, S., Galvani, A. and Isacchi, A. (2014) The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol. Oncol. 8, 1495-1507. https://doi.org/10.1016/j.molonc.2014.06.001
  3. Ardini, E., Menichincheri, M., Banfi, P., Bosotti, R., De Ponti, C., Pulci, R., Ballinari, D., Ciomei, M., Texido, G., Degrassi, A., Avanzi, N., Amboldi, N., Saccardo, M. B., Casero, D., Orsini, P., Bandiera, T., Mologni, L., Anderson, D., Wei, G., Harris, J., Vernier, J. M., Li, G., Felder, E., Donati, D., Isacchi, A., Pesenti, E., Magnaghi, P. and Galvani, A. (2016) Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol. Cancer Ther. 15, 628-639. https://doi.org/10.1158/1535-7163.MCT-15-0758
  4. Bongarzone, I., Pierotti, M. A., Monzini, N., Mondellini, P., Manenti, G., Donghi, R., Pilotti, S., Grieco, M., Santoro, M. and Fusco, A. (1989) High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 4, 1457-1462.
  5. Cagnol, S. and Chambard, J.-C. (2010) ERK and cell death: mechanisms of ERK-induced cell death - apoptosis, autophagy and senescence. FEBS J. 277, 2-21. https://doi.org/10.1111/j.1742-4658.2009.07366.x
  6. Cho, S. Y., Han, S. Y., Ha, J. D., Ryu, J. W., Lee, C. O., Jung, H., Kang, N. S., Kim, H. R., Koh, J. S. and Lee, J. (2010) Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors. Bioorg. Med. Chem. Lett. 20, 4223-4227. https://doi.org/10.1016/j.bmcl.2010.05.031
  7. Chou, T. C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55. https://doi.org/10.1016/0065-2571(84)90007-4
  8. Chung, H. J., Park, K. R., Lee, H. J., Lee, J., Kim, J. H., Kim, Y. C. and Han, S. Y. (2015) Effects of KRC-108 on the Aurora A activity and growth of colorectal cancer cells. Biochem. Biophys. Res. Commun. 461, 605-611. https://doi.org/10.1016/j.bbrc.2015.04.073
  9. Cocco, E., Scaltriti, M. and Drilon, A. (2018) NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 15, 731-747. https://doi.org/10.1038/s41571-018-0113-0
  10. Dadakhujaev, S., Jung, E. J., Noh, H. S., Hah, Y. S., Kim, C. J. and Kim, D. R. (2009) Interplay between autophagy and apoptosis in TrkA-induced cell death. Autophagy 5, 103-105. https://doi.org/10.4161/auto.5.1.7276
  11. Dadakhujaev, S., Noh, H. S., Jung, E. J., Hah, Y.-S., Kim, C. J. and Kim, D. R. (2008) The reduced catalase expression in TrkA-induced cells leads to autophagic cell death via ROS accumulation. Exp. Cell Res. 314, 3094-3106. https://doi.org/10.1016/j.yexcr.2008.08.013
  12. Doebele, R. C., Davis, L. E., Vaishnavi, A., Le, A. T., Estrada-Bernal, A., Keysar, S., Jimeno, A., Varella-Garcia, M., Aisner, D. L., Li, Y., Stephens, P. J., Morosini, D., Tuch, B. B., Fernandes, M., Nanda, N. and Low, J. A. (2015) An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 5, 1049-1057. https://doi.org/10.1158/2159-8290.CD-15-0443
  13. Doebele, R. C., Drilon, A., Paz-Ares, L., Siena, S., Shaw, A. T., Farago, A. F., Blakely, C. M., Seto, T., Cho, B. C., Tosi, D., Besse, B., Chawla, S. P., Bazhenova, L., Krauss, J. C., Chae, Y. K., Barve, M., Garrido-Laguna, I., Liu, S. V., Conkling, P., John, T., Fakih, M., Sigal, D., Loong, H. H., Buchschacher, G. L., Jr., Garrido, P., Nieva, J., Steuer, C., Overbeck, T. R., Bowles, D. W., Fox, E., Riehl, T., Chow-Maneval, E., Simmons, B., Cui, N., Johnson, A., Eng, S., Wilson, T. R. and Demetri, G. D.; trial investigators (2020) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 21, 271-282. https://doi.org/10.1016/s1470-2045(19)30691-6
  14. Franke, T. F., Hornik, C. P., Segev, L., Shostak, G. A. and Sugimoto, C. (2003) PI3K/Akt and apoptosis: size matters. Oncogene 22, 8983-8998. https://doi.org/10.1038/sj.onc.1207115
  15. Han, S. Y. (2021) TRK Inhibitors: tissue-agnostic anti-cancer drugs. Pharmaceuticals (Basel) 14, 632. https://doi.org/10.3390/ph14070632
  16. Han, S. Y., Lee, C. O., Ahn, S. H., Lee, M. O., Kang, S. Y., Cha, H. J., Cho, S. Y., Ha, J. D., Ryu, J. W., Jung, H., Kim, H. R., Koh, J. S. and Lee, J. (2012) Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo. Invest. New Drugs 30, 518-523. https://doi.org/10.1007/s10637-010-9584-2
  17. Hansen, K., Wagner, B., Hamel, W., Schweizer, M., Haag, F., Westphal, M. and Lamszus, K. (2007) Autophagic cell death induced by TrkA receptor activation in human glioblastoma cells. J. Neurochem. 103, 259-275. https://doi.org/10.1111/j.1471-4159.2007.04753.x
  18. Harada, G., Gongora, A. B. L., da Costa, C. M. and Santini, F. C. (2020) TRK inhibitors in non-small cell lung cancer. Curr. Treat. Options Oncol. 21, 39. https://doi.org/10.1007/s11864-020-00741-z
  19. Hirose, M., Kuroda, Y. and Murata, E. (2016) NGF/TrkA signaling as a therapeutic target for pain. Pain Pract. 16, 175-182. https://doi.org/10.1111/papr.12342
  20. Jorgensen, J. T. (2020) Site-agnostic biomarker-guided oncology drug development. Expert Rev. Mol. Diagn. 20, 583-592. https://doi.org/10.1080/14737159.2020.1702521
  21. Khotskaya, Y. B., Holla, V. R., Farago, A. F., Mills Shaw, K. R., MericBernstam, F. and Hong, D. S. (2017) Targeting TRK family proteins in cancer. Pharmacol. Ther. 173, 58-66. https://doi.org/10.1016/j.pharmthera.2017.02.006
  22. Kondo, Y., Kanzawa, T., Sawaya, R. and Kondo, S. (2005) The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer 5, 726-734. https://doi.org/10.1038/nrc1692
  23. Levy, J. M. M., Towers, C. G. and Thorburn, A. (2017) Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528-542. https://doi.org/10.1038/nrc.2017.53
  24. Martin-Zanca, D., Hughes, S.H. and Barbacid, M. (1986) A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319, 743-748. https://doi.org/10.1038/319743a0
  25. Medico, E., Russo, M., Picco, G., Cancelliere, C., Valtorta, E., Corti, G., Buscarino, M., Isella, C., Lamba, S., Martinoglio, B., Veronese, S., Siena, S., Sartore-Bianchi, A., Beccuti, M., Mottolese, M., Linnebacher, M., Cordero, F., Di Nicolantonio, F. and Bardelli, A. (2015) The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat. Commun. 6, 7002. https://doi.org/10.1038/ncomms8002
  26. Menichincheri, M., Ardini, E., Magnaghi, P., Avanzi, N., Banfi, P., Bossi, R., Buffa, L., Canevari, G., Ceriani, L., Colombo, M., Corti, L., Donati, D., Fasolini, M., Felder, E., Fiorelli, C., Fiorentini, F., Galvani, A., Isacchi, A., Borgia, A. L., Marchionni, C., Nesi, M., Orrenius, C., Panzeri, A., Pesenti, E., Rusconi, L., Saccardo, M. B., Vanotti, E., Perrone, E. and Orsini, P. (2016) Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor. J. Med. Chem. 59, 3392-3408. https://doi.org/10.1021/acs.jmedchem.6b00064
  27. Noh, H. S., Hah, Y. S., Zada, S., Ha, J. H., Sim, G., Hwang, J. S., Lai, T. H., Nguyen, H. Q., Park, J. Y., Kim, H. J., Byun, J. H., Hahm, J. R., Kang, K. R. and Kim, D. R. (2016) PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. Autophagy 12, 2183-2196. https://doi.org/10.1080/15548627.2016.1219013
  28. Okamura, R., Boichard, A., Kato, S., Sicklick, J. K., Bazhenova, L. and Kurzrock, R. (2018) Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis. Oncol. 2018, PO.18.00183.
  29. Onorati, A. V., Dyczynski, M., Ojha, R. and Amaravadi, R. K. (2018) Targeting autophagy in cancer. Cancer 124, 3307-3318. https://doi.org/10.1002/cncr.31335
  30. Pan, H., Wang, Z., Jiang, L., Sui, X., You, L., Shou, J., Jing, Z., Xie, J., Ge, W., Cai, X., Huang, W. and Han, W. (2014) Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib. Sci. Rep. 4, 6683. https://doi.org/10.1038/srep06683
  31. Reichardt, L. F. (2006) Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1545-1564. https://doi.org/10.1098/rstb.2006.1894
  32. Scott, L. J. (2019) Larotrectinib: first global approval. Drugs 79, 201-206. https://doi.org/10.1007/s40265-018-1044-x