抗癌药物PARP抑制剂获得性耐药的进化研究

聚（ADP-核糖）聚合酶小分子抑制剂（PARPi）是一类新型有效的抗肿瘤靶向药物，但其获得性耐药是一个严重的临床问题，并且我们对PARPi 获得性耐药进化机制知之甚少。基于多种选择压力的存在，我们提出假说：不同来源的选择压力影响PARPi 获得性耐药的进化过程，导致不同耐药特征。初期研究显示：作为一条重要的DNA 双链断离修复途径，同源重组（HR）参与PARPi 获得性耐药进化。此外，根据进化适应成本理论，主要耐药突变会损害细胞增殖，导致临床耐药性和敏感性之间的反复。因此，耐药细胞往往需要补偿突变以弥补受损的细胞增殖能力，导致持续性耐药。为了深入探索PARPi 获得性耐药进化机制及相应临床问题，我们将：1）分析 HR 在对不同PARPi 获得耐药后的变化；2）分析辅助药物对HR 水平的影响；3）检测PARPi 获得性耐药克隆的细胞增殖能力；4）鉴定PARPi 获得性耐药主突变和补偿突变。

BRCA1- and BRCA2-deficient human breast cancers are defective for the major DNA double strand break repair pathway homologous recombination (HR). Exploitation of this HR vulnerability has led to the recent development of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as a new class of anti-tumor drugs for the treatment of BRCA1- and BRCA2-deficient breast cancers. PARPi also show utility for treating cancers not deficient for HR. Despite preliminary success in clinical trials, acquired resistance to PARPi may invariably occur and, in fact, is beginning to be observed, posing a serious clinical problem for this PARPi-based cancer therapy. According to the tumor evolution theory, acquisition of resistance to PARPi is a fundamentally evolutionary process. However, as the evolutionary aspect has long been overlooked in the field, it is no surprise that little is known about the evolution of acquired resistance to different PARPi. Due to varying properties of different PARPi, heterogeneity of targeted tumors and different mechanisms of action of combining drugs, we hypothesize: the selective pressure imposed by different PARPi may influence the evolution of acquired resistance to PARPi by selecting or inducing certain gene mutations, resulting in different resistance traits. Interestingly, our preliminry studies raise a possibility that HR enhancement may be a common outcome of primary resistance mutations selected or induced by treatment with PARPi. Based on the concept of fitness cost in the evolution theory, primary resistance mutations tend to impair cell proliferation of resistant clones, likely resuming tumor sensitivity to PARPi in clinics after acquiring resistance to PARPi. However, because of long-term continuous treatment with PARPi, resistant tumor cells can acquire additional compensatory mutations to compensate for the impairment of their proliferation, resulting in persistent resistance in patients. To further elucidate the molecular mechanisms of the evolution of acquired resistance to PARPi and address the related clinical problems, we will: 1) Analyze HR during development of acquired resistance to different PARPi; 2) Determine effect of combining drugs on HR during development of acquired resistance to PARPi ; 3) Analyze cell proliferation of PARPi-resistant clones; 4) Identify both primary resistance mutations and compensatory mutations that promote acquired resistance to PARPi. This project will not only advance the study of the evolution of acquired resistance to PARPi at the molecular level, but also have significant clinical relevance.