CHMFL-BMX-078, a BMX inhibitor, overcomes the resistance of melanoma to vemurafenib via inhibiting AKT pathway. (5th January 2022)

• Record Type: Journal Article
• Authors: Jiang, ShiLong; Jiang, Ting; Huang, HanXue; Chen, XiSha; Li, LanYa; Wang, ZhiBin; Fei, JiangFeng; Liu, Chong; Liu, ZhaoQian; Cheng, Yan
• Is Part Of: Chemico-biological interactions. Volume 351(2022)
• Publication Date: 2022-01-05
• Subjects: eIF3a Eukaryotic Translation Initiation Factors 3a -- BMX Bone Marrow Kinase on Chromosome X -- AKT Protein Kinase B -- EGFR Epidermal Growth Factor Receptor -- TKI Tyrosine Kinase Inhibitors; Melanoma -- Vemurafenib resistance -- BMX -- CHMFL-BMX-078 -- AKT; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109747
• Languages: English
• ISSNs: 0009-2797

Abstract

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. Graphical abstract: Our findings demonstrate that the BMX inhibitor CHMFL-BMX-078 selectively inhibits vemurafenib-resistant melanoma cell proliferation and induces cell cycle arrest by suppressing the AKT signaling pathway. Therefore, combined CHMFL-BMX-078 and vemurafenib was identified as a potential strategy to treat vemurafenib resistance. Image 1 Highlights: CHMFL-BMX-078 selectively inhibited the growth of vemurafenib-resistant cells. CHMFL-BMX-078 enhanced vemurafenib sensitivity by suppression of AKT pathway. CHMFL-BMX-078 could overcome the resistance of vemurafenib in vitro and in vivo.