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. (1) 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.

靶向癌症治疗通常依赖于抑制肿瘤细胞的有益适应。例如，抑制互补或补偿机制可以将细胞推向生存边缘。临床上使用的此类干预的一个例子是抑制聚（二磷酸腺苷-核糖）聚合酶 (PARP)，以治疗通过同源重组途径（突变的BRCA1或BRCA2基因）导致 DNA 修复受损的肿瘤。尽管对使用 PARP 抑制剂 (PARPi) 的治疗产生了总体有益的反应，但耐药性仍然是一个令人生畏的问题。尽管已经广泛探索了对 PARPi 敏化剂的搜索，但仍需要新的组合来改善反应。在本期的第 156 页，Fugger等人。( 1) 发现干扰核苷酸代谢会增强 PARPi 在同源重组受损癌细胞中的功效。这一发现为提高 PARPi 功效开辟了几条有希望的途径，甚至有望克服获得性耐药性。