2. Academic Validation
  3. CHMFL-BMX-078, a BMX inhibitor, overcomes the resistance of melanoma to vemurafenib via inhibiting AKT pathway

CHMFL-BMX-078, a BMX inhibitor, overcomes the resistance of melanoma to vemurafenib via inhibiting AKT pathway

  • Chem Biol Interact. 2022 Jan 5;351:109747. doi: 10.1016/j.cbi.2021.109747.
ShiLong Jiang 1,  Ting Jiang 2,  HanXue Huang 1,  XiSha Chen 2,  LanYa Li 2,  ZhiBin Wang 1,  JiangFeng Fei 3,  Chong Liu 1,  ZhaoQian Liu 4,  Yan Cheng 5
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, PR China.
  • 2 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, PR China.
  • 3 Sinocare Inc., Changsha, 410000, PR China.
  • 4 Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, PR China. Electronic address: zqliu@csu.edu.cn.
  • 5 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, PR China. Electronic address: yancheng@csu.edu.cn.
PMID: 34813779 DOI: 10.1016/j.cbi.2021.109747
Abstract

Our recent study demonstrated eIF3a loss contributes to vemurafenib resistance in melanoma by activating ERK. However, overexpression of eIF3a in the clinic is not feasible to produce vemurafenib re-sensitization, and ERK inhibitors combined with vemurafenib still exhibit limited effectiveness in the treatment of melanoma. Here, using the human receptor tyrosine kinase phosphorylation antibody array, we observed that silencing eIF3a could activate BMX, a tyrosine kinase. The BMX inhibitor CHMFL-BMX-078 could significantly suppress proliferation and induce cell cycle arrest in vemurafenib resistant melanoma cell line A375 (A375R), however, it was hypotoxic in immortal keratinocytes, melanoma cells, and other solid Cancer cells such as glioma and breast Cancer cells. Furthermore, the combined treatment of CHMFL-BMX-078 and vemurafenib synergistically reduced cell viability and restored the sensitivity of resistant cells to vemurafenib. The reversal of the resistant phenotype by CHMFL-BMX-078 was associated with the Akt signaling pathway, as co-treatment with the Akt Activator SC-79 or up-regulation of Akt attenuated the anti-proliferation effect of CHMFL-BMX-078 and vemurafenib. Lastly, we demonstrated that CHMFL-BMX-078 could significantly enhance vemurafenib efficacy in a xenograft model of A375R cells without producing additive toxicity. In conclusion, these findings reveal that the BMX inhibitor CHMFL-BMX-078 may reverse vemurafenib resistance in melanoma by suppressing the Akt signaling pathway, implying that CHMFL-BMX-078 may be a promising compound for overcoming vemurafenib resistance.

Keywords

AKT; BMX; CHMFL-BMX-078; Melanoma; Vemurafenib resistance.

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