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

Simple Summary 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. Abstract 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.