J Cancer 2021; 12(21):6356-6362. doi:10.7150/jca.60845 This issue

Research Paper

TRK inhibitors block NFKB and induce NRF2 in TRK fusion-positive colon cancer

Sung-Hwa Sohn1, Hee Jung Sul1, Bohyun Kim1, Bum Jun Kim2, Hyeong Su Kim2, Dae Young Zang1,2✉

1. Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea.
2. Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea.

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Citation:
Sohn SH, Sul HJ, Kim B, Kim BJ, Kim HS, Zang DY. TRK inhibitors block NFKB and induce NRF2 in TRK fusion-positive colon cancer. J Cancer 2021; 12(21):6356-6362. doi:10.7150/jca.60845. Available from https://www.jcancer.org/v12p6356.htm

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Abstract

Graphic abstract

Tropomyosin receptor kinase (TRK) fusion is one of the oncogenic driver causes of colon cancer, and tropomyosin 3-neurotrophic receptor tyrosine kinase 1 (TPM3-NTRK1) fusion has been detected in the KM12SM cell line. In the present study, we investigated anticancer mechanisms in the KM12SM cell line using three different form of dovitinib (dovitinib (free base), dovitinib lactate (mono acid), and dovitinib dilactic acid (diacid)) and four TRK inhibitors (LOXO-101, entrectinib, regorafenib, and crizotinib). Exposure of TRK inhibitors at concentrations of 10 nM resulted in the apoptosis of KM12SM cells, whereas regorafenib had no effect. Treatment with all inhibitors except regorafenib also significantly increased the expression levels of the genes nuclear factor-erythroid 2-related factor 2 (NRF2) and glutamyl cysteine ligase catalytic subunit (GCLC) in KM12SM. These drugs significantly reduced expression of the phosphorylated proteins NFκB and COX-2 in the KM12SM cell line, and significantly attenuated KM12SM cell migration, according to a Transwell migration assay. Together, these results suggest that TRK inhibitors block products of carcinogenesis by negatively regulating the NFκB signaling pathway and positively regulating the antioxidant NRF2 signaling pathway.

Keywords: TPM3-NTRK1, TRK inhibitors, NRF2, NFκB