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.
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, PR China.
Chem Biol Interact. 2022 Jan 5;351:109747. doi: 10.1016/j.cbi.2021.109747. Epub 2021 Nov 20.
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 的缺失通过激活 ERK 导致黑色素瘤对vemurafenib 产生耐药性。然而，在临床上过表达 eIF3a 并不可行，无法使 vemurafenib 重新敏感，并且 ERK 抑制剂与 vemurafenib 联合使用在治疗黑色素瘤方面仍然效果有限。在这里，我们使用人类受体酪氨酸激酶磷酸化抗体阵列观察到，沉默 eIF3a 可以激活酪氨酸激酶 BMX。BMX 抑制剂 CHMFL-BMX-078 可显著抑制vemurafenib 耐药黑色素瘤细胞系 A375（A375R）的增殖，并诱导细胞周期停滞，然而，它在永生化角质形成细胞、黑色素瘤细胞和其他实体癌细胞如神经胶质瘤和乳腺癌细胞中具有低毒性。此外，CHMFL-BMX-078 与 vemurafenib 的联合治疗可协同降低细胞活力并恢复耐药细胞对 vemurafenib 的敏感性。CHMFL-BMX-078 逆转耐药表型与 AKT 信号通路有关，因为与 AKT 激活剂 SC-79 共同处理或上调 AKT 减弱了 CHMFL-BMX-078 和 vemurafenib 的抗增殖作用。最后，我们证明 CHMFL-BMX-078 可在 A375R 细胞的异种移植模型中显著增强 vemurafenib 的疗效，而不会产生附加毒性。总之，这些发现表明，BMX 抑制剂 CHMFL-BMX-078 可能通过抑制 AKT 信号通路逆转黑色素瘤对 vemurafenib 的耐药性，这表明 CHMFL-BMX-078 可能是克服 vemurafenib 耐药性的有前途的化合物。
