Baquero Juan Miguel, Marchena-Perea Erik, Mirabet Rocío, Torres-Ruiz Raúl, Blanco-Aparicio Carmen, Rodríguez-Perales Sandra, Helleday Thomas, Benítez-Buelga Carlos, Benítez Javier, Osorio Ana
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Front Oncol. 2022 May 10;12:888810. doi: 10.3389/fonc.2022.888810. eCollection 2022.
PARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.
We hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.
Knocking out in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of deficiency, reflecting an additive interaction.
These results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in -deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.
PARP1在碱基切除修复（BER）途径中起关键作用，在BRCA缺陷的情况下，PARP1抑制通过合成致死相互作用导致特定细胞死亡。迄今为止，已有多达五种不同的PARP抑制剂（PARPi）被批准，然而，对PARPi产生耐药性很常见，人们越来越关注增强反应并将其应用扩展到其他肿瘤类型。
我们假设其他BER成员可能是与突变BRCA基因的额外合成致死伙伴。为了验证这一点，我们决定通过用PARPi奥拉帕利和OGG1抑制剂TH5478处理BRCA1功能正常和缺陷的乳腺癌细胞，来评估糖基化酶OGG1作为潜在候选者。
在三阴性乳腺癌细胞系中敲除OGG1会导致对OGG1抑制剂TH5487过敏。此外，TH5487增强了对PARP抑制剂奥拉帕利的敏感性，特别是在BRCA缺陷的情况下，反映出一种累加相互作用。
这些结果提供了首个证据，即OGG1抑制在BRCA缺陷细胞中是一种有前景的新合成致死策略，并可能为遗传性乳腺癌和卵巢癌的治疗带来新框架。
