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

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.

Similar additive effects of doxorubicin in combination with photon or proton irradiation in soft tissue sarcoma models

“…However, management of STS is increasingly subtype-dependent and resistance for Dox is present. Resistance mediating molecular alterations such as the mutation of TP53 was discussed since p53-dependent apoptosis is the main mechanism of action of Dox ( 32 ).Unfortunately, the investigation of new molecular targets only showed an incremental progress and no superior effect relative to Dox ( 13 ). Nevertheless, patients with undifferentiated pleomorphic sarcoma (UPS, GCT cells) showed the highest overall response from treatment with monoclonal antibodies against PD-L1 ( 33 ).…”

“…In our study, GCT and RD cells showed a pronounced resistance to Dox treatment of any schedule, which can in part be explained by the mutated TP53 gene. In primary STS cultures, a high mutation rate in apoptotic signaling genes (TP53, ATM, PIK3CB, PIK3R1, NTRK1, CSF2RB) was found and linked to Dox resistance ( 32 ). Future experiments should include molecular analysis regarding apoptosis and migration biomarkers to understand the additive effects mediated by anthracycline-based regimen.…”

“…When comparing the different Dox schedules, DoxB and DoxC were superior to DoxA. Dox and ifosfamide remain the most effective chemotherapy drugs available for STS tumors (31). However, management of STS is increasingly subtype-dependent and resistance for Dox is present.…”

Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers

“…Indeed, TP53 mutation in patients with breast cancer is associated with primary resistance to doxorubicin therapy [31]; the loss of functional p53 protein confers resistance to etoposide in neuroblastoma and glioma cells [32,33]. Moreover, transfection with wild-type p53 sensitizes soft tissue sarcoma cells to doxorubicin [34]. Considering these previous observations and the present study, it is suggested that p53 signaling regulates topoisomerase inhibitor sensitivity, supporting our results that p53 regulation via the nucleolar stress response is involved in topoisomerase inhibitor sensitivity.…”

Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy

“…The data obtained from some STS cell lines [5] are not in full agreement with the results of tumor analysis of STS patients [6]. Although the mutation rate is low in STS [7], a number of studies have revealed a relationship between the development of resistance to Dox and the presence of mutations in the apoptosis activation pathway [8]. It has been found that in ChT-resistant STS samples, the expression of genes involved in signaling pathways associated with cell adhesion, migration, proliferation, cytotaxis, and phagocytosis, as well as signaling cascades PI3K-Akt, NF-κB, MAPK, and Jak -STAT is activated.…”