Kirilin Evgeny M, Fetisov Timur I, Moiseeva Natalia I, Lesovaya Ekaterina A, Laletina Lidia A, Makhmudova Leyla F, Manikaylo Angelika E, Fomina Liliya Y, Burov Denis A, Bokhyan Beniamin Yu, Zinovieva Victoria Y, Vilkova Alice S, Mekheda Larisa V, Kozlov Nikolay A, Scherbakov Alexander M, Belitsky Gennady A, Švedas Vytas, Kirsanov Kirill I, Yakubovskaya Marianna G
Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1, 119991 Moscow, Russia.
N.N. Blokhin NMRCO, 115478 Moscow, Russia.
Cancers (Basel). 2022 Apr 1;14(7):1796. doi: 10.3390/cancers14071796.
Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in , and . Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling.
软组织肉瘤（STS）是一种异质性癌症，有100多种组织学亚型，分子改变各不相同，这使得其个性化治疗非常复杂。晚期STS化疗的金标准包括阿霉素与异环磷酰胺或吉西他滨与多西他赛的联合使用。化疗对不到50%的患者有效，且随后会迅速产生耐药性。我们的研究旨在寻找与未分化多形性和滑膜肉瘤对上述基因毒性药物的化疗耐药相关的癌细胞基因改变。我们使用原发性STS培养物在体外分析癌细胞的化疗耐药性，并对凋亡信号通路的成分进行基因分析。在27%的肿瘤中，我们发现了 、 和 的改变。来自具有上述基因改变的STS标本的细胞对阿霉素耐药，但排除了唯一一例TP53突变导致Leu344Arg替代且与部分寡聚化丧失相关且未导致TP53功能完全丧失的情况。发现凋亡信号通路成分的改变与对阿霉素的化疗耐药之间存在显著关联。我们的数据对于进一步制定具有凋亡信号通路改变的STS患者的治疗策略很重要。
