Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.
Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.
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尽管PARP抑制剂（PARPi）已被证明是一种有前景的抗癌药物，用于BRCA1/2突变的癌症患者，但它在BRCA1/2突变发生率低的结直肠癌患者中提供的临床益处有限。在我们的研究中，我们发现PARPi talazoparib通过抑制p53泛素化和激活p21显著诱导细胞衰老。此外，CDK4/6i palbociclib在体外和体内增强了这种治疗诱导的衰老（TIS）。在机制上，talazoparib和palbociclib联合诱导衰老相关分泌表型（SASP）， SASP成分的表征揭示了I型干扰素（IFN）相关介质，这些介质通过cGAS/STING信号放大。更重要的是，RNA测序数据表明，联合治疗激活了T细胞特征，联合治疗将肿瘤微环境（TME）转化为更抗肿瘤的状态，CD8 T细胞和自然杀伤细胞（NK）增加，巨噬细胞和粒细胞骨髓源性抑制细胞（G - MDSCs）减少。此外，αPD‐L1清除TIS细胞可促进免疫活性小鼠结直肠癌模型的存活。总的来说，我们阐明了talazoparib-palbociclib联合的协同抗肿瘤和免疫调节机制。进一步联合PD‐L1抗体可能是一种有希望的“一举两得”的结直肠癌治疗策略。Talazoparib和palbociclib联合可触发治疗诱导的衰老并激活抗肿瘤免疫，从而增强免疫检查点阻断治疗在结直肠癌中的抗癌作用。衰老相关分泌表型成分的表征揭示了I型IFN相关介质，这些介质通过cGAS/STING信号放大。
Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy‐induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence‐associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)‐related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid‐derived suppressor cells (G‐MDSCs). Moreover, clearance of the TIS cells by αPD‐L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib–palbociclib combination. Further combination with PD‐L1 antibody might be a promising “one‐two punch” therapeutic strategy for colorectal cancer patients. Talazoparib and palbociclib combination triggers therapy‐induced senescence and activates antitumor immunity, which strengthens the anticancer effect of immune checkpoint blockade treatment in colorectal cancer. Characterization of senescence‐associated secretory phenotype components reveals type I IFN‐related mediators, which are amplified by cGAS/STING signaling.
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影响因子：
13.6
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3.3
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