Overcoming resistance of stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47Δ and immune checkpoint inhibitors.
Overcoming resistance of stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47Δ and immune checkpoint inhibitors.
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DOI：
10.1016/j.omto.2022.12.001
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发表时间：
2023-03-16
期刊：
影响因子：
--
通讯作者：
Todo, Tomoki
中科院分区：
文献类型：
--
作者：
Yamada, Tomoharu;Tateishi, Ryosuke;Iwai, Miwako;Tanaka, Minoru;Ijichi, Hideaki;Sano, Makoto;Koike, Kazuhiko;Todo, Tomoki
胰腺导管腺癌（PDAC）是一种以其致密的肿瘤间质而闻名的致死性疾病。粘着斑激酶抑制剂（FAKi）是一种非受体型酪氨酸激酶抑制剂，可减少肿瘤间质。G47Δ是第三代溶瘤性单纯疱疹病毒1型，选择性杀伤肿瘤细胞并诱导抗肿瘤免疫应答。本研究评估FAKi和G47Δ在PDAC模型中与或不与免疫检查点抑制剂组合的功效。G47Δ在体外和皮下以及原位肿瘤模型中对人PDAC细胞系有效。转基因小鼠衍生的#146细胞用于在免疫活性小鼠中产生具有丰富基质的皮下PDAC肿瘤。在该#146肿瘤模型中，当与G47Δ组合时，FAKi的功效协同增强，这不仅反映了基质含量降低，而且反映了肿瘤微环境向免疫刺激的显著转变。在转基因本地PKF小鼠中，一种罕见的模型，其产生具有100%转化率的富含基质的PDAC，并且在各个方面类似于人PDAC，与单独FAKi相比，只有当FAKi与G47Δ和免疫检查点抑制剂组合时，才实现存活期的延长。FAKi组合疗法可用于克服富含基质的PDAC的治疗抗性。黏着斑激酶抑制剂联合溶瘤性疱疹病毒G47Δ和免疫检查点抑制剂可克服富间质胰腺导管腺癌的治疗耐药性。FAKi减少转基因小鼠中PDAC的基质，允许有效的免疫细胞浸润。联合治疗有效地将肿瘤微环境转向免疫刺激。
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease known for its dense tumor stroma. Focal adhesion kinase inhibitor (FAKi), a non-receptor type tyrosine kinase inhibitor, reduces the tumor stroma. G47Δ, a third-generation oncolytic herpes simplex virus type 1, destroys tumor cells selectively and induces antitumor immune responses. This study evaluates the efficacy of FAKi and G47Δ in PDAC models in combination with or without immune checkpoint inhibitors. G47Δ was effective in human PDAC cell lines in vitro and in subcutaneous as well as orthotopic tumor models. Transgenic mouse-derived #146 cells were used to generate subcutaneous PDAC tumors with rich stroma in immunocompetent mice. In this #146 tumor model, the efficacy of FAKi was synergistically augmented when combined with G47Δ, which reflected not only a decreased stromal content but also a significant shifting of the tumor microenvironment toward immune stimulation. In transgenic autochthonous PKF mice, a rare model that develops stroma-rich PDAC with a 100% penetrance and resembles human PDAC in various aspects, the prolongation of survival compared with FAKi alone was achieved only when FAKi was combined with G47Δ and immune checkpoint inhibitors. The FAKi combination therapy may be useful to overcome the treatment resistance of stroma-rich PDAC. Therapeutic resistance of stroma-rich pancreatic ductal adenocarcinoma can be overcome by focal adhesion kinase inhibitor combined with oncolytic herpes virus G47Δ and immune checkpoint inhibitors. FAKi reduces the stroma of PDAC in transgenic mice, allowing efficient immune cell infiltration. The combination therapy effectively shifts the tumor microenvironment toward immune stimulation.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
64.5
作者：
Serrels A;Lund T;Serrels B;Byron A;McPherson RC;von Kriegsheim A;Gómez-Cuadrado L;Canel M;Muir M;Ring JE;Maniati E;Sims AH;Pachter JA;Brunton VG;Gilbert N;Anderton SM;Nibbs RJ;Frame MC
通讯作者：
Frame MC
DOI：
10.17140/poj-3-e010
发表时间：
2019-01-01
期刊：
Pancreas (Fairfax, Va.)
影响因子：
--
作者：
Hakim, Nausheen;Patel, Rajvi;Saif, Muhammad W
通讯作者：
Saif, Muhammad W
影响因子：
2.9
作者：
Ko AH;LoConte N;Tempero MA;Walker EJ;Kate Kelley R;Lewis S;Chang WC;Kantoff E;Vannier MW;Catenacci DV;Venook AP;Kindler HL
通讯作者：
Kindler HL
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA