PO.ET02.11 · 实验与分子治疗
以首创的双模式药物克服PD-1抵抗，将"冷"肿瘤转化为"热"肿瘤
Overcoming PD-1 resistance with a first-in-class dual-mode agent that transforms ‘cold' tumors to ‘hot'
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫检查点阻断在大多数结直肠癌（CRC）中失败，因为它们在免疫学上是"冷"的且错配修复功能正常（pMMR）。这与错配修复缺陷（dMMR）的"热"肿瘤形成鲜明对比，后者高度应答；新辅助抗PD-1治疗在早期dMMR CRC中实现了100%的临床完全缓解。这种深刻的差异凸显了迫切需要一种策略，以在治疗上将pMMR肿瘤转化为dMMR样状态。目前的方法缺乏在细胞水平上诱导并维持这种转化所必需的协调机制。
方法：我们设计了一组双模式药物，对单个肿瘤细胞施加两种协同打击，直接和间接地破坏DNA错配修复（MMR）MSH2/6基因。使用实时微卫星不稳定性（MSI）报告基因筛选，我们鉴定了能够从机制上诱导高MSI（MSI-H）表型的先导化合物。随后在对PD-1阻断产生抵抗的pMMR CRC小鼠模型中评估了最有前景的候选物。
结果：我们鉴定了BDB025，一种强效的、首创的双模式药物，它在诱导强健的MSI-H表型的同时，通过表观遗传学方式沉默关键的MMR基因。至关重要的是，这种dMMR样转化是在极低的、亚细胞毒性剂量下实现的，展示了一种独特的非细胞死亡介导的作用机制。这种在同一细胞内协调的双管齐下攻击压垮了DNA错配修复机制，特别是MSH2/MSH6，增加了肿瘤突变负荷和T细胞浸润。因此，BDB025将"冷"pMMR肿瘤转化为"热"肿瘤，消除已建立的肿瘤，并克服对抗PD-1治疗的抵抗，显著优于标准药物。
结论：我们展示了一种范式转变的治疗策略：一种单一分子通过协同利用两种协同的作用机制，在药理学上诱导合成的dMMR状态。我们的先导候选物BDB025有效打破PD-1抵抗，为将免疫治疗的治愈潜力扩展到庞大的pMMR癌症患者群体铺平了道路。
关键词：PD-1抵抗、结直肠癌、MSI-H、DNA错配修复、MSH2、MSH6
查看英文原文 English abstract
Background: Immune checkpoint blockade fails in most colorectal cancers (CRCs) because they are immunologically ‘cold' and mismatch repair-proficient (pMMR). This stands in stark contrast to mismatch repair-deficient (dMMR) ‘hot' tumors, which are highly responsive; neoadjuvant anti-PD-1 achieves a 100% clinical complete response in early-stage dMMR CRC. This profound disparity underscores the urgent need for a strategy to therapeutically convert pMMR tumors into a dMMR-like state. Current approaches lack the coordinated mechanism necessary to induce and sustain this conversion at the cellular level.
Methods: We have designed a panel of dual-mode agents to deliver two synergistic insults to individual tumor cells, directly and indirectly disrupting DNA mismatch repair (MMR) MSH2/6 genes. Using a real-time microsatellite instability (MSI) reporter screen, we identified lead compounds that mechanistically induce a high MSI (MSI-H) phenotype. The most promising candidate was subsequently evaluated in murine models of pMMR CRC resistant to PD-1 blockade.
Results: We identified BDB025, a potent, first-in-class dual-mode agent that induces a robust MSI-H phenotype while simultaneously epigenetically silencing critical MMR genes. Crucially, this dMMR-like conversion is achieved at very low, sub-cytotoxic dosages, demonstrating a unique non-cell-death-mediated mechanism of action. This coordinated, two-pronged attack within the same cell overwhelms the DNA mismatch repair machinery, specifically MSH2/MSH6 , increases tumor mutational burden and T cell influx. Consequently, BDB025 converts ‘cold' pMMR tumors to ‘hot', ablates established tumors, and overcomes resistance to anti-PD-1 therapy, significantly outperforming standard agents.
Conclusion: We demonstrate a paradigm-shifting therapeutic strategy: a single molecule that pharmacologically induces a synthetic dMMR state by co-opting two synergistic mechanisms of action. Our lead candidate, BDB025, effectively breaks PD-1 resistance, paving the way to extend the curative potential of immunotherapy to the vast population of patients with pMMR cancers.
Keywords: PD-1 resistance, colorectal cancer, MSI-H, DNA mismatch repair, MSH2, MSH6
利益披露 Disclosure
T. Zhu, None..
L. Li, None.