Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by conferring more or less potency in the killing of tumor cells. To identify such modifiers, isogenic cell lines were utilized to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoptosis. It was found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a pan-aurora kinase inhibitor, VX-680. Suppression was show to stem from the inhibition of autophagy, specifically in multinucleated cells, rather than a general inhibition of apoptosis. The anti-autophagic activity of Bcl-2 also impacted polyploid cell recovery in colony-forming assays, suggesting a route of escape from MYC-VX-680 synthetic lethality that may have clinical consequences. These findings expand on previous conclusions that autophagic death of VX-680-induced polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs.

抑制Aurora-B激酶是一种过度表达MYC癌蛋白的肿瘤的合成致死疗法。目前尚不清楚共同发生的致癌性改变是否会通过赋予肿瘤细胞杀伤力或多或少的能力来影响这种合成杀伤力。为了鉴定此类修饰物，同基因细胞系用于测试多种癌症基因，这些基因先前已证明可在细胞应激条件下促进存活，促进化学耐药性和/或抑制MYC引发的凋亡。已发现，Bcl-2家族的两个抗凋亡成员Bcl-2和Bcl-xL可以部分抑制泛极光激酶抑制剂VX-680引起的合成致死性，但不能抑制多核化。已显示抑制作用源于自噬的抑制，特别是在多核细胞中，而不是一般地抑制凋亡。Bcl-2的抗自噬活性也影响了菌落形成试验中多倍体细胞的恢复，这表明摆脱MYC-VX-680合成杀伤力的途径可能会产生临床后果。这些发现扩展了以前的结论，即Atg6介导VX-680诱导的多倍体细胞的自噬死亡。Bcl-2和Bcl-xL负调节MYC-VX-680合成杀伤力，这是这两个Bcl-2家族蛋白（特别是在多核细胞中）的抗自噬活性，有助于抵抗针对Aurora激酶的药物。这些发现扩展了以前的结论，即Atg6介导VX-680诱导的多倍体细胞的自噬死亡。Bcl-2和Bcl-xL负调节MYC-VX-680合成杀伤力，这是这两个Bcl-2家族蛋白（特别是在多核细胞中）的抗自噬活性，有助于抵抗针对Aurora激酶的药物。这些发现扩展了以前的结论，即Atg6介导VX-680诱导的多倍体细胞的自噬死亡。Bcl-2和Bcl-xL负调节MYC-VX-680合成杀伤力，这是这两个Bcl-2家族蛋白（特别是在多核细胞中）的抗自噬活性，有助于抵抗针对Aurora激酶的药物。