Anticancer Biosciences and the J. Michael Bishop Institute of Cancer Research, Chengdu, China.
Chengdu University of Traditional Chinese Medicine, Chengdu, China.
PLoS One. 2021 Mar 24;16(3):e0248355. doi: 10.1371/journal.pone.0248355. eCollection 2021.
A synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug's inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic or epigenomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases, ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC.
当癌症相关变化为癌细胞引入独特的脆弱性，使它们对药物的抑制活性异常敏感时，就会产生合成致死效应。合成致死方法很有吸引力，因为它可以针对特定基因组或表观基因组改变的癌症进行靶向治疗，这些改变的产物可能对直接靶向治疗具有抗性。一个例子是由 MYC 过表达驱动的癌症。在这里，我们使用小分子文库对升高的 MYC 具有合成致死作用的化合物进行了高内涵筛选，以鉴定与调节批准药物密切相关或本身就是调节批准药物的化合物。该筛选鉴定出二甲基法舒地尔，这是一种 Rho 相关激酶 ROCK1 和 ROCK2 的有效且可逆抑制剂。二甲基法舒地尔的类似物临床上用于治疗神经和心血管疾病。该合成致死相互作用在啮齿动物和人类细胞系中是保守的，并且可以通过 MYC 或其同源物 MYCN 的激活来观察到。这种合成致死性似乎特异性地针对 MYC 过表达细胞，因为它不能被多种致癌操作所替代，并且在人类癌细胞系中通过 RNAi 介导的 MYC 耗竭可以降低合成致死性。总之，这些数据支持研究使用二甲基法舒地尔作为一种对特异性过表达 MYC 的恶性肿瘤具有合成致死作用的药物。
