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Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer
Cell Communication and Signaling ( IF 8.2 ) Pub Date : 2021-05-17 , DOI: 10.1186/s12964-021-00733-y
Ari Hashimoto 1 , Haruka Handa 1 , Soichiro Hata 1 , Akio Tsutaho 1, 2 , Takao Yoshida 3 , Satoshi Hirano 2 , Shigeru Hashimoto 1, 4 , Hisataka Sabe 1
Affiliation  

Many clinical trials are being conducted to clarify effective combinations of various drugs for immune checkpoint blockade (ICB) therapy. However, although extensive studies from multiple aspects have been conducted regarding treatments for pancreatic ductal adenocarcinoma (PDAC), there are still no effective ICB-based therapies or biomarkers for this cancer type. A series of our studies have identified that the small GTPase ARF6 and its downstream effector AMAP1 (also called ASAP1/DDEF1) are often overexpressed in different cancers, including PDAC, and closely correlate with poor patient survival. Mechanistically, the ARF6-AMAP1 pathway drives cancer cell invasion and immune evasion, via upregulating β1-integrins and PD-L1, and downregulating E-cadherin, upon ARF6 activation by external ligands. Moreover, the ARF6-AMAP1 pathway enhances the fibrosis caused by PDAC, which is another barrier for ICB therapies. KRAS mutations are prevalent in PDACs. We have shown previously that oncogenic KRAS mutations are the major cause of the aberrant overexpression of ARF6 and AMAP1, in which KRAS signaling enhances eukaryotic initiation factor 4A (eIF4A)-dependent ARF6 mRNA translation and eIF4E-dependent AMAP1 mRNA translation. MYC overexpression is also a key pathway in driving cancer malignancy. MYC mRNA is also known to be under the control of eIF4A, and the eIF4A inhibitor silvestrol suppresses MYC and ARF6 expression. Using a KPC mouse model of human PDAC (LSL-Kras(G12D/+); LSL-Trp53(R172H/+)); Pdx-1-Cre), we here demonstrate that inhibition of the ARF6-AMAP1 pathway by shRNAs in cancer cells results in therapeutic synergy with an anti-PD-1 antibody in vivo; and furthermore, that silvestrol improves the efficacy of anti-PD-1 therapy, whereas silvestrol on its own promotes tumor growth in vivo. ARF6 and MYC are both essential for normal cell functions. We demonstrate that silvestrol substantially mitigates the overexpression of ARF6 and MYC in KRAS-mutated cells, whereas the suppression is moderate in KRAS-intact cells. We propose that targeting eIF4A, as well as mutant KRAS, provides novel methods to improve the efficacy of anti-PD-1 and associated ICB therapies against PDACs, in which ARF6 and AMAP1 overexpression, as well as KRAS mutations of cancer cells are biomarkers to identify patients with drug-susceptible disease. The same may be applicable to other cancers with KRAS mutations.

中文翻译:


eIF4A 抑制剂药物抑制突变型 KRAS 驱动的 ARF6 和 MYC 过表达可改善胰腺癌的抗 PD-1 免疫疗法的效果



许多临床试验正在进行中,以阐明免疫检查点阻断(ICB)疗法中各种药物的有效组合。然而,尽管对胰腺导管腺癌(PDAC)的治疗进行了多方面的广泛研究,但仍然没有针对这种癌症类型的有效的基于ICB的疗法或生物标志物。我们的一系列研究发现,小 GTP 酶 ARF6 及其下游效应子 AMAP1(也称为 ASAP1/DDEF1)通常在包括 PDAC 在内的不同癌症中过度表达,并且与患者生存率较差密切相关。从机制上讲,ARF6-AMAP1 通路在外部配体激活 ARF6 后,通过上调 β1-整合素和 PD-L1 并下调 E-钙粘蛋白,驱动癌细胞侵袭和免疫逃避。此外,ARF6-AMAP1通路会增强PDAC引起的纤维化,这是ICB治疗的另一个障碍。 KRAS 突变在 PDAC 中普遍存在。我们之前已经表明,致癌的 KRAS 突变是 ARF6 和 AMAP1 异常过度表达的主要原因,其中 KRAS 信号传导增强真核起始因子 4A (eIF4A) 依赖性 ARF6 mRNA 翻译和 eIF4E 依赖性 AMAP1 mRNA 翻译。 MYC 过度表达也是导致癌症恶性的关键途径。还已知 MYC mRNA 受到 eIF4A 的控制,而 eIF4A 抑制剂 silvestrol 可抑制 MYC 和 ARF6 的表达。 使用人类 PDAC 的 KPC 小鼠模型 (LSL-Kras(G12D/+);LSL-Trp53(R172H/+)); Pdx-1-Cre),我们在此证明,癌细胞中 shRNA 对 ARF6-AMAP1 通路的抑制可与体内抗 PD-1 抗体产生治疗协同作用;此外,西维甾醇可提高抗PD-1疗法的功效,而西维甾醇本身可促进体内肿瘤生长。 ARF6 和 MYC 对于正常细胞功能都是必需的。我们证明,西维甾醇可显着减轻 KRAS 突变细胞中 ARF6 和 MYC 的过度表达,而在 KRAS 完整细胞中,这种抑制作用是中等的。我们认为,针对 eIF4A 以及突变型 KRAS 提供了新的方法来提高抗 PD-1 和相关 ICB 疗法对 PDAC 的疗效,其中 ARF6 和 AMAP1 过表达以及癌细胞的 KRAS 突变是 PDAC 的生物标志物。识别患有药物敏感疾病的患者。这同样可能适用于具有 KRAS 突变的其他癌症。
更新日期:2021-05-17
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