In Vivo Targeting Replication Protein A for Cancer Therapy.
In Vivo Targeting Replication Protein A for Cancer Therapy.
复制标题
DOI：
10.3389/fonc.2022.826655
复制
发表时间：
2022
影响因子：
4.7
通讯作者：
Pawelczak KS
中科院分区：
文献类型：
--
作者：
VanderVere-Carozza PS;Gavande NS;Jalal SI;Pollok KE;Ekinci E;Heyza J;Patrick SM;Masters A;Turchi JJ;Pawelczak KS
复制蛋白A（RPA）在DNA复制、修复、重组和DNA损伤反应（DDR）中起重要作用。肺癌患者数据的回顾性分析表明，RPA高表达是吸烟相关肺癌总生存率的负预后生物标志物。类似地，RPA的相对表达是对化疗反应的预测标志物。这些观察结果与RPA表达的增加一致，RPA表达作为一种适应性机制，允许耐受致癌物暴露引起的遗传毒性应激。我们已经开发了第二代RPA抑制剂（RPA），阻断RPA-DNA相互作用，并优化了体内分析的配方。数据表明，与第一代RPA不同，第二代分子显示出增加的细胞渗透性并通过凋亡诱导细胞死亡。第二代RPA在广泛的癌症中引发单一药剂的体外抗癌活性，并且细胞应答表明在化学RPA耗尽诱导细胞死亡之前存在阈值。化学RPA抑制增强了一系列DDR抑制剂和传统DNA损伤癌症治疗剂的抗癌活性。与化学RPA耗尽一致，我们证明了RPAi对复制叉动力学的影响与其他已知的DDR抑制剂相似。开发了RPAi NERx 329的优化制剂，在两种非小细胞肺癌模型中产生了单药抗癌活性。这些数据证明了RPA的独特作用机制，引发化学RPA耗尽的状态，并表明它们将为难以治疗的肺癌提供有效的治疗选择。
Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers.
登录
查看更多内容
影响因子：
14.8
作者：
Exell JC;Thompson MJ;Finger LD;Shaw SJ;Debreczeni J;Ward TA;McWhirter C;Siöberg CL;Martinez Molina D;Abbott WM;Jones CD;Nissink JW;Durant ST;Grasby JA
通讯作者：
Grasby JA
影响因子：
14.9
作者：
Gavande NS;VanderVere-Carozza PS;Pawelczak KS;Mendoza-Munoz P;Vernon TL;Hanakahi LA;Summerlin M;Dynlacht JR;Farmer AH;Sears CR;Nasrallah NA;Garrett J;Turchi JJ
通讯作者：
Turchi JJ
影响因子：
4
作者：
Neher, Tracy M.;Shuck, Sarah C.;Turchi, John J.
通讯作者：
Turchi, John J.
影响因子：
16
作者：
Toledo, Luis;Neelsen, Kai John;Lukas, Jiri
通讯作者：
Lukas, Jiri
影响因子：
--
作者：
Arora S;Heyza J;Zhang H;Kalman-Maltese V;Tillison K;Floyd AM;Chalfin EM;Bepler G;Patrick SM
通讯作者：
Patrick SM