三振出局，破解乳腺癌突变耐药难题
乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，一旦发生突变，容易引起乳腺癌等恶性肿瘤，尤其多见于三阴性乳腺癌。由于BRCA1和BRCA2突变可影响脱氧核糖核酸（DNA）损伤修复相关信号传导通路，故此类患者通常对多腺苷二磷酸核糖聚合酶（PARP）抑制剂敏感，但是可能继发耐药。寻找新的方法在耐药产生之前有效杀死癌细胞或恢复其敏感性，对于提高患者生存机会至关重要。
2021年4月9日，全球自然科学三大期刊之一、美国科学促进会《科学》正刊发表英国伦敦弗朗西斯克里克研究所、德国慕尼黑大学的研究报告，通过全基因组筛选，发现对核苷酸清除因子DNPH1进行抑制，可增强或恢复BRCA突变癌细胞对PARP抑制剂的敏感性。
DNPH1是一种蛋白质，可清除具有杀死癌细胞作用的核苷酸——羟甲脱氧尿苷单磷酸，阻止这种异常核苷酸掺入癌细胞DNA。该研究表明，对DNPH1进行抑制，可增强BRCA突变癌细胞对PARP抑制剂的敏感性。单链单功能尿嘧啶DNA糖基化酶SMUG1对基因组羟甲脱氧尿苷的合成致死作用，可引起PARP捕获、DNA复制叉折叠、DNA断裂形成和凋亡。利用羟甲脱氧尿苷和DNPH1抑制剂，可恢复继发耐药BRCA1突变细胞对PARP抑制剂的敏感性。
因此，该研究结果表明，基因组羟甲脱氧尿苷是PARP抑制剂敏感性的关键决定因素，羟甲脱氧尿苷＋DNPH1抑制剂＋PARP抑制剂有望成为破解BRCA突变癌耐药的新策略。
对此，英国牛津大学路德維希癌症研究所发表同期评论：表观遗传核苷酸可强化治疗。
Science. 2021 Apr 9;372(6538):156-165.
Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors.
Kasper Fugger, Ilirjana Bajrami, Mariana Silva Dos Santos, Sarah Jane Young, Simone Kunzelmann, Geoff Kelly, Graeme Hewitt, Harshil Patel, Robert Goldstone, Thomas Carell, Simon J. Boulton, James Macrae, Ian A. Taylor, Stephen C. West.
The Francis Crick Institute, London, UK; Ludwig-Maximilians-Universitat München, Munich, Germany.
Three strikes to knock cancer out: BRCA1 and BRCA2 are tumor-suppressor genes, and patients with mutations in these genes are predisposed to breast, ovarian, and other cancers. Because BRCA1 and BRCA2 mutations affect pathways involved in DNA break repair, these patients' tumors are usually vulnerable to treatments that further damage DNA repair, such as poly(ADP-ribose) polymerase (PARP) inhibitors, but they can acquire resistance to therapy. Using a genome-wide screening approach, Fugger et al. identified a protein called DNPH1 as a “nucleotide sanitizer” that prevents the incorporation of abnormal nucleotides into DNA (see the Perspective by Kriaucionis). The authors examined its mechanism of action and demonstrated how it can be targeted to expedite the killing of BRCA1-mutant cancer cells in combination with PARP inhibitor treatment.
Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.
DOI: 10.1126/science.abb4542
Science. 2021 Apr 9;372(6538):127-128.
Epigenetic nucleotides enhance therapy.
Skirmantas Kriaucionis.
Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
Targeted cancer therapy often relies on inhibiting beneficial adaptations of tumor cells. For example, inhibiting complementary or compensatory mechanisms can push cells over the edge of survival. An example of this kind of intervention, which is used in the clinic, is inhibition of poly(adenosine diphosphate-ribose) polymerase (PARP) for treatment of tumors with compromised DNA repair by the homologous recombination pathway (mutated BRCA1 or BRCA2 genes). Despite overall beneficial response to treatment with PARP inhibitors (PARPi), resistance is still a formidable problem. Although the search for PARPi sensitizers has been extensively explored, new combinations to improve responses are needed. On page 156 of this issue, Fugger et al found that interference with nucleotide metabolism potentiates the efficacy of PARPi in homologous recombination-compromised cancer cells. This discovery opens several promising avenues to enhance PARPi efficacy and could even hold promise for overcoming acquired resistance.
DOI: 10.1126/science.abh3188