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.

我们最近的研究表明，eIF3a 缺失通过激活 ERK 导致黑色素瘤中维莫非尼耐药。然而，临床上eIF3a的过度表达并不可行以产生威罗非尼再敏化，并且ERK抑制剂联合威罗非尼在黑色素瘤的治疗中仍然表现出有限的有效性。在这里，使用人类受体酪氨酸激酶磷酸化抗体阵列，我们观察到沉默 eIF3a 可以激活酪氨酸激酶 BMX。 BMX 抑制剂 CHMFL-BMX-078 可以显着抑制威罗非尼耐药黑色素瘤细胞系 A375 (A375R) 的增殖并诱导细胞周期停滞，但在永生角质形成细胞、黑色素瘤细胞和其他实体癌细胞（例如神经胶质瘤和乳腺癌）中毒性较低癌细胞。此外，CHMFL-BMX-078和维罗非尼联合治疗可协同降低细胞活力并恢复耐药细胞对维罗非尼的敏感性。 CHMFL-BMX-078 对耐药表型的逆转与 AKT 信号通路有关，因为与 AKT 激活剂 SC-79 共同治疗或上调 AKT 减弱了 CHMFL-BMX-078 的抗增殖作用，并且维莫非尼。最后，我们证明 CHMFL-BMX-078 可以显着增强 A375R 细胞异种移植模型中维莫非尼的疗效，而不产生附加毒性。总之，这些研究结果表明，BMX 抑制剂 CHMFL-BMX-078 可能通过抑制 AKT 信号通路来逆转黑色素瘤中的维莫非尼耐药性，这意味着 CHMFL-BMX-078 可能是克服维莫非尼耐药性的有前途的化合物。