Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments

Abstract

Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation.

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

“…The authors then screened known inhibitors of NER genes in order to find compounds that could increase cisplatin sensitization in vivo. NSC130813 and triptolide improved cisplatin efficacy in resistant and sensitive cell lines and displayed no evidence of cross-resistance with cisplatin [373]. These agents warrant further testing in a clinical setting.…”

“…Hence, targeting genes and proteins involved in the NER and BER pathway could provide an opportunity to circumvent resistance based on enhanced DNA repair mechanisms. A recent study by Fanelli and colleagues showed that silencing of ERCC1, ERCC2, ERCC3, ERCC4, or XPA was able to increase cisplatin sensitivity in the resistant U2-OS/CDDP300 and U2-OS/CDDP1 cells, and that silencing of ERCC1, ERCC2, or ERCC4 increased cisplatin sensitivity in the parental cell line U2-OS [373]. The authors then screened known inhibitors of NER genes in order to find compounds that could increase cisplatin sensitization in vivo.…”

“…These kinases include FGFR1, MAP2K3, MAPK1, MAPK3, and PIC3C3. A screen of possible kinase inhibitors found that GDC0994 (targeting the MAPK pathway) and PD173074 (targeting FGFR1) were able to reduce the IC50 of cisplatin in resistant osteosarcoma cell lines [373]. Though further testing is needed, use of these compounds could be useful in sensitizing resistant osteosarcoma to standard treatment.…”

Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

“…One attractive treatment strategy could include targeting NER factors. Fanelli and colleagues (2020) recently found that two compounds, NSC130813 (NERI02; F06) and triptolide, which inhibit DNA repair through binding of DNA repair proteins, enhance sensitivity to cisplatin in U2OS and Saos2 cells [ 190 ]. Understanding how these factors function in the context of mechanotransduction could aid in the success of NSC130813 (NERI02; F06) and triptolide in treating refractory OSA patients.…”

Curcumin Derivative C086 Combined with Cisplatin Inhibits Proliferation of Osteosarcoma Cells

“…BMIL1 is highly expressed in osteosarcoma cells, and its overexpression promotes cell growth and chemotherapeutic resistance to cisplatin in osteosarcoma [ 23 ]. Cisplatin is a commonly used chemotherapeutic drug in patients with osteosarcoma, but it often causes drug resistance, so the effects of chemotherapy are not ideal [ 24 , 25 ]. However, the exact role played by BMIL1 in osteosarcoma treated with curcumin and cisplatin is not fully understood.…”