Halaban Ruth, Bacchiocchi Antonella, Straub Robert, Cao Jian, Sznol Mario, Narayan Deepak, Allam Ahmed, Krauthammer Michael, Mansour Tarek S
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Oncotarget. 2019 Mar 19;10(23):2237-2251. doi: 10.18632/oncotarget.26787.
The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth . As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.
使用BRAF和MAPK抑制剂治疗黑色素瘤的主要缺点是存在先天性和获得性耐药性。因此，我们探索了其他靶点并开发了一种新化合物SAB298，它是一种SRC家族激酶（SFK）抑制剂。该药物对源自患者的黑色素瘤细胞具有细胞毒性，无论癌基因表达情况如何，并且能抑制肿瘤生长。正如预期的那样，它抑制了SRC和PI3K活性，还具有抑制ERBB2的特性，这导致两种ERK磷酸酶PP2A和SHP2失活。在57%的测试黑色素瘤细胞系中，ERK活性的相应增加导致其底物——谱系特异性转录因子MITF发生蛋白水解降解，这可能有助于生长停滞。联合使用SAB298和AZD6244（司美替尼）进行治疗，可诱导协同生长抑制，这表明这种新化合物可在临床上用作MAPK抑制剂的替代品或与之联合使用。
