Abstract
BackgroundThe response of soft tissue sarcomas to cytotoxic chemotherapy is inconsistent. Biomarkers of chemoresistance or chemosensitivity are needed in order to identify appropriate patients for treatment. Given that many chemotherapeutics kill cells through direct DNA interactions, we hypothesized that upregulation of DNA damage response mechanisms would confer resistance to cytotoxic chemotherapy in sarcomas. To study this, we used spontaneously-occurring feline injection-site sarcomas (FISS).MethodsγH2AX and p53 expression were determined in biopsy samples of FISS. γH2AX expression was determined via immunohistochemistry whereas p53 expression was determined via qRT-PCR. Cell lines derived from these sarcoma biopsies were then treated with carboplatin (N = 11) or doxorubicin (N = 5) and allowed to grow as colonies. Colony forming-ability of cells exposed to chemotherapy was compared to matched, untreated cells and expressed as percent survival relative to controls. ImageJ was used for quantification. A mixed model analysis was performed to determine if an association existed between relative survival of the treated cells and γH2AX or p53 expression in the original tumors. Cell lines were validated via vimentin expression or growth as subcutaneous sarcomas in nude mice.ResultsAn association was detected between γH2AX expression and relative survival in cells exposed to carboplatin (P = 0.0250). In the 11 FISS tumors evaluated, γH2AX expression ranged from 2.2 to 18.8% (mean, 13.3%). Cells from tumors with γH2AX expression higher than the sample population mean had fourfold greater relative survival after carboplatin exposure than cells from tumors with γH2AX expression less than the mean. There was no association between relative survival after carboplatin exposure and p53 expression (P = 0.1608), and there was no association between relative survival after doxorubicin exposure and either γH2AX (P = 0.6124) or p53 (P = 0.8645) expression. Four cell lines were validated via growth as sarcomas in nude mice. Vimentin expression was confirmed in the other 7 cell lines.ConclusionsγH2AX expression, but not wild type p53, may potentially serve as a biomarker of resistance to platinum therapeutics in soft tissue sarcomas. To further investigate this finding, prospective, in vivo studies are indicated in animal models.
Highlights
The response of soft tissue sarcomas to cytotoxic chemotherapy is inconsistent
Chemotherapeutic drugs approved by the US Food and Drug Administration for the treatment of Soft tissue sarcomas (STS) include anthracyclines such as doxorubicin as well as other agents such as eribulin, trabectedin, and ifosfamide, but convincing data demonstrating improved outcomes is lacking in the adjuvant setting, studies are frequently underpowered for meaningful analysis [5, 6]
It is possible that alterations in DNA damage response (DDR) pathways are not involved in resistance to doxorubicin in the feline injection-site sarcomas (FISS) cells we investigated, we analyzed a limited number of cell lines, and these particular cell lines were rather sensitive to the doxorubicin concentrations used, limiting the overall power of this aspect of our analysis
Summary
The response of soft tissue sarcomas to cytotoxic chemotherapy is inconsistent. Biomarkers of chemoresistance or chemosensitivity are needed in order to identify appropriate patients for treatment. In a meta-analysis, adjuvant chemotherapy including doxorubicin was associated with increased time to local and distant recurrence; there was no impact on overall survival (HR, 0.89; 95% CI, 0.76–1.03; P = 0.12) [7]. An updated meta-analysis, including four additional trials, found reduced overall recurrence (P = 0.0001) with either adjuvant doxorubicin alone, adjuvant doxorubicin-based chemotherapy, or adjuvant doxorubicin-based chemotherapy combined with ifosfamide [8]. In this updated analysis, a reduction in overall mortality in patients receiving adjuvant chemotherapy was detected (HR, 0.77; 95% CI, 0.64–0.93; P = 0.01), the impact was relatively small with an absolute risk reduction from 46 to 40%. Little progress has been made with respect to targeted therapeutics, the multi-tyrosine kinase inhibitor pazopanib is approved for adults with advanced soft tissue sarcoma that have received prior chemotherapy [14]
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