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Article

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin

1
Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1, 119991 Moscow, Russia
2
N.N. Blokhin NMRCO, 115478 Moscow, Russia
3
Department of Oncology, I.P. Pavlov Ryazan State Medical University, 390026 Ryazan, Russia
4
Research Computing Center, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, 119991 Moscow, Russia
5
Institute of Medicine, RUDN University, 117198 Moscow, Russia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Academic Editor: Adam C. Berger
Cancers 2022, 14(7), 1796; https://doi.org/10.3390/cancers14071796
Received: 7 February 2022 / Revised: 15 March 2022 / Accepted: 30 March 2022 / Published: 1 April 2022
Genotoxic chemotherapy is the main component of the treatment for advanced soft tissue sarcomas. However, its efficacy is rather low and it is followed by rapid appearance of drug resistance. Our study was directed to the search of molecular drivers of chemoresistance in synovial and undifferentiated pleomorphic sarcomas to genotoxic drugs mostly used for their treatment. Using primary cell cultures obtained from sarcomas after surgery, we estimated their chemoresistance in vitro and performed exome sequencing. We revealed that cancer cells of more than one quarter of patients had molecular alterations preventing apoptosis and observed an association between molecular alterations found and chemoresistance to Doxorubicin, but not to Ifosfamide or Gemcitabine and Docetaxel. Information concerning the peculiar drivers of individual drug resistance could help to improve personalized chemotherapy by withdrawal from an inefficient drug or by targeting the revealed mechanism of chemoresistance.
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 TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. 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. View Full-Text
Keywords: soft tissue sarcoma; undifferentiated pleomorphic sarcoma; synovial sarcoma; chemoresistance; Doxorubicin; Ifosfamide; Gemcitabine; Docetaxel; genetic alterations; apoptotic signaling soft tissue sarcoma; undifferentiated pleomorphic sarcoma; synovial sarcoma; chemoresistance; Doxorubicin; Ifosfamide; Gemcitabine; Docetaxel; genetic alterations; apoptotic signaling
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MDPI and ACS Style

Kirilin, E.M.; Fetisov, T.I.; Moiseeva, N.I.; Lesovaya, E.A.; Laletina, L.A.; Makhmudova, L.F.; Manikaylo, A.E.; Fomina, L.Y.; Burov, D.A.; Bokhyan, B.Y.; Zinovieva, V.Y.; Vilkova, A.S.; Mekheda, L.V.; Kozlov, N.A.; Scherbakov, A.M.; Belitsky, G.A.; Švedas, V.; Kirsanov, K.I.; Yakubovskaya, M.G. Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin. Cancers 2022, 14, 1796. https://doi.org/10.3390/cancers14071796

AMA Style

Kirilin EM, Fetisov TI, Moiseeva NI, Lesovaya EA, Laletina LA, Makhmudova LF, Manikaylo AE, Fomina LY, Burov DA, Bokhyan BY, Zinovieva VY, Vilkova AS, Mekheda LV, Kozlov NA, Scherbakov AM, Belitsky GA, Švedas V, Kirsanov KI, Yakubovskaya MG. Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin. Cancers. 2022; 14(7):1796. https://doi.org/10.3390/cancers14071796

Chicago/Turabian Style

Kirilin, Evgeny M., Timur I. Fetisov, Natalia I. Moiseeva, Ekaterina A. Lesovaya, Lidia A. Laletina, Leyla F. Makhmudova, Angelika E. Manikaylo, Liliya Y. Fomina, Denis A. Burov, Beniamin Yu. Bokhyan, Victoria Y. Zinovieva, Alice S. Vilkova, Larisa V. Mekheda, Nikolay A. Kozlov, Alexander M. Scherbakov, Gennady A. Belitsky, Vytas Švedas, Kirill I. Kirsanov, and Marianna G. Yakubovskaya. 2022. "Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin" Cancers 14, no. 7: 1796. https://doi.org/10.3390/cancers14071796

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