德克萨斯大学安德森癌症中心Gordon B. Mills课题组近日取得一项新成果。研究认为使用PARP和WEE1抑制剂的序贯治疗在保持疗效的同时将毒性降到最低。 这一研究成果于2019年6月10日发表在《Cancer Cell》上。

该团队证明，同时使用多聚(ADP-核糖) 聚合酶(PARP)和WEE1抑制剂能够有效抑制肿瘤生长，但耐受性较差。同时使用PARP和WEE1抑制剂治疗可诱导正常细胞和恶性细胞的复制应激、DNA损伤，并破坏G2 DNA损伤检查点。在停止使用PARP或WEE1抑制剂的单一治疗后，这些抑制剂的作用仍然存在，这表明序次使用PARP和WEE1抑制剂可以在改善毒性的同时保持疗效。值得注意的是，虽然序贯给药反映了同时治疗在癌细胞中具有高基础复制应激，但正常细胞的低基础复制压力保护了它们免受DNA损伤和毒性，因此，在提高耐受性的同时，保留了卵巢癌异种移植和患者来源的异种移植模型的疗效。

附：英文原文

Title: Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy

Author: Yong Fang, Daniel J. McGrail, Chaoyang Sun, Mark J. O''Connor, Timothy A. Yap, Gordon B. Mills

Issue&Volume: Jun 10, 2019 Volume 35Issue 6

Abstract: We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.

DOI: https://doi.org/10.1016/j.ccell.2019.05.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30224-7