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

ABSTRACT

Introduction: DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients.

Area covered: In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed.

Expert opinion: Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.

KEYWORDS:

• ABC transporters
• detoxification
• DNA damage
• DNA repair
• ERCC1
• germline polymorphisms
• GST
• pharmacogenetics
• osteosarcoma
• toxicity

Article highlights

• Several drugs used in HGOS treatment cause DNA damages, which can be repaired by different pathways.

• Highly efficient DNA repair is an important mechanism for therapeutic resistance and its impairment due to germline genetic variations can be associated with higher sensitivity and toxicity predisposition to DNA damaging drugs.

• Polymorphisms of genes involved in metabolism and transport of DNA damaging drugs used in HGOS chemotherapy could help to determine which patients are more responsive to chemotherapy and may also predict patients’ predisposition to treatment related toxicity and adverse drug reactions.

• The gene polymorphisms emerged from studies in which HGOS patients were treated with the first-line drugs may exhibit clinical relevance also when treatment is based on drugs used in rescue chemotherapy protocols.

• Paired genetic analyses on both normal and tumor cells are necessary to identify HGOS patients who may benefit from synthetic lethality approaches aimed to improve tumor sensitivity to DNA damaging drugs without increasing adverse toxicity. Unfortunately, pharmacogenetics applied to HGOS still suffers from the lack of comparative studies between tumor and normal cells.

This box summarizes key points contained in the article.

Acknowledgments

The authors’ studies and preliminary findings cited in this manuscript were supported by grants from the Italian Association for Cancer Research (funding from AIRC under IG 2018 - ID. 21487 project – P.I. Serra Massimo), Italian Ministry of Health Project RF-2016-02361373, and Istituto Ortopedico Rizzoli (5 x mille contributions to the Rizzoli Institute).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.