Current understanding of pharmacogenetic implications of DNA damaging drugs used in osteosarcoma treatment

Hattinger, Claudia Maria; Patrizio, Maria Pia; Luppi, Silvia; Magagnoli, Federica; Picci, Piero; Serra, Massimo

doi:10.1080/17425255.2019.1588885

Cited by 12 publications

(11 citation statements)

References 63 publications

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“…Consequently, the ability of tumor cells to repair drug-induced DNA damages significantly impacts upon efficacy of these compounds (7,8,10,11). Accordingly, the expression and activity of factors belonging to DNA repair pathways have been demonstrated to be involved in chemotherapy response and patients' outcome in different human tumors (7,8,12), with few findings also reported for OS (4,9). This body of evidence has also indicated components related to DNA repair pathways as promising targets for innovative anticancer therapies, and several drugs interfering with these systems have entered phases I-II-III clinical trials (11,17,18).…”

Section: Discussionmentioning

confidence: 99%

“…High-grade OS is usually treated with neoadjuvant chemotherapy protocols based on cisplatin (CDDP), doxorubicin, methotrexate, and ifosfamide. However, despite this aggressive approach, 35-45% of patients still recur and experience an unfavorable outcome (1)(2)(3)(4)(5).…”

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confidence: 99%

“…Among these drugs, CDDP is the agent which has most extensively been studied in relation to DNA repair. A consistent body of evidence is showing that the onset of clinical unresponsiveness to CDDP usually creates further therapeutic complications, because patients can also become cross-resistant to the other DNA damaging chemotherapeutic drugs used in first-or rescue treatment protocols (4,6).…”

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confidence: 99%

“…One of the most important mechanisms of resistance against CDDP is repair of drug-induced DNA damages via different pathways, of which the most common is the nucleotide excision repair (NER) (4,7,8). We have recently obtained data indicating that protein overexpression of the NER gene ERCC excision repair 1 (ERCC1) negatively impacts on the clinical responsiveness to CDDP-based treatments and on patients' outcome (9).…”

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confidence: 99%

“…In addition to NER, other DNA repair pathways, first of all the base excision repair (BER), have been indicated or proved to be implicated in CDDP resistance of several human tumors (10)(11)(12), but their relative impact significantly varies among different neoplasms and only very few information is available for OS (4).…”

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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European standard clinical practice recommendations for children and adolescents with primary and recurrent osteosarcoma

van Ewijk,

Herold,

Baecklund

et al. 2023

EJC Paediatric Oncology

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Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling

Martin

Reiche

Fifelski

et al. 2020

Biochemical Journal

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Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched-chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes. The cytosolic branched-chain aminotransferase (BCATc) that is commonly overexpressed in cancer cells, was down-regulated in chondrosarcoma (SW1353) in contrast with osteosarcoma (143B) cells that expressed both BCATc and its mitochondrial isoform BCATm. Treating SW1353 cells with gabapentin, a selective inhibitor of BCATc, further revealed that these cells failed to respond to gabapentin. Application of the structural analog of leucine, N-acetyl-leucine amide (NALA) to disrupt leucine uptake, indicated that all bone sarcoma cells used leucine to support their energy metabolism and biosynthetic demands. This was evident from the increased activity of the energy sensor AMP-activated protein kinase (AMPK), down-regulation of complex 1 of the mammalian target of rapamycin (mTORC1), and reduced cell viability in response to NALA. The observed changes were most profound in the 143B cells, which appeared highly dependent on cytosolic and mitochondrial BCAA metabolism. This study thus demonstrates that bone sarcomas rely on leucine and BCAA metabolism for energy and growth; however, the differential expression of BCAA enzymes and the presence of other carbon sources may dictate how efficiently these cancer cells take advantage of BCAA metabolism.

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Current understanding of pharmacogenetic implications of DNA damaging drugs used in osteosarcoma treatment

Cited by 12 publications

References 63 publications

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

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

European standard clinical practice recommendations for children and adolescents with primary and recurrent osteosarcoma

Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling

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