MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors.
MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors.
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MEK 抑制重塑突变 KRAS 肿瘤的免疫景观，以克服对 PARP 和免疫检查点抑制剂的耐药性
DOI：
10.1158/0008-5472.can-20-2370
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发表时间：
2021-05-15
期刊：
影响因子：
11.2
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Yang B;Li X;Fu Y;Guo E;Ye Y;Li F;Liu S;Xiao R;Liu C;Lu F;Huang J;Qin T;Han L;Peng G;Mills GB;Sun C;Chen G
这项研究为使用Meki联合PARPI和抗PD-L1治疗所有突变的KRAS肿瘤的可能性提供了关键的见解。突变的KRAS肿瘤与不良预后有关，至少部分原因是治疗敏感性降低。在这里，我们表明KRAS突变与对PARP抑制剂(PARPI)的单一治疗和联合治疗以及抗PD-L1抗体的免疫检查点阻断的耐药性有关。在突变的KRAS肿瘤中，用MEK抑制剂(Meki)抑制KRAS信号触发并放大了PARPI诱导的DNA损伤、胞浆双链DNA积聚、STING通路激活和CD8+T细胞募集。此外，Meki通过抑制IL6和GMCSF的产生，减少了髓系来源的抑制细胞的渗透。重要的是，在免疫活性突变的KRAS肿瘤模型中，将Meki加入PARPI和抗PD-L1导致显著的肿瘤抑制。这项研究为PARPI、Meki和抗PD-L1联合用于突变KRAS肿瘤的临床试验提供了潜在的机制数据。意义：这项研究为使用Meki联合PARPI和抗PD-L1治疗所有突变的KRAS肿瘤的可能性提供了关键的见解。图形摘要：http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.图形摘要
This study provides key insights into the potential for using MEKi combined with PARPi and anti-PD-L1 for the treatment of all mutant KRAS tumors. Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti–PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti–PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti–PD-L1 combination in clinical trials of mutant KRAS tumors. Significance: This study provides key insights into the potential for using MEKi combined with PARPi and anti–PD-L1 for the treatment of all mutant KRAS tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg. Graphical Abstract