Treatment May Be Harmful: Mechanisms/Prediction/Prevention of Drug-Induced DNA Damage and Repair in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a malignancy characterized by accumulation of malignant plasma cells within the bone marrow (BM). MM is considered mostly without definitive treatment because of the inability of standard of care therapies to overcome drug-resistant relapse. Genotoxic agents are used in the treatment of MM and exploit the fact that DNA double-strand breaks are highly cytotoxic for cancer cells. However, their mutagenic effects are well-established and described. According to these effects, chemotherapy could cause harmful DNA damage associated with new driver genomic abnormalities providing selective advantage, drug resistance, and higher relapse risk. Several mechanisms associated with MM cell (MMC) resistance to genotoxic agents have been described, underlining MM heterogeneity. The understanding of these mechanisms provides several therapeutic strategies to overcome drug resistance and limit mutagenic effects of treatment in MM. According to this heterogeneity, adopting precision medicine into clinical practice, with the development of biomarkers, has the potential to improve MM disease management and treatment.

Keywords: DNA damage; drug resistance; genomic instability; genotoxic agents; multiple myeloma.

Figure 1

Mechanisms involved in DNA-damaging drug resistance in MM. Overview of mechanisms contributing to resistance to DNA-damaging agents in MM, including cellular extrusion of the drugs by ATP-dependent pumps, decreased drug influx, increased drug inactivation by metabolism, inactivation of apoptotic pathways, enhanced DNA repair, and altered cell cycle checkpoints and cell communication signals provided by the microenvironment.

Figure 2

DNA single-strand damage repair. Base damages are repaired by base excision repair, bulky adducts by nucleotide excision repair, and base mismatch by mismatch repair pathway.

Figure 3

DNA interstrand crosslink repair. ICL repair can be initiated either at a stalled RNA polymerase (A) or at a replication fork (B). (A) ICLs in DNA will stall RNA polymerase during transcription. The RNA polymerase will either backtrack or be degraded during subsequent repair involving translesion (TLS) polymerases and NER pathway. (B) The removal of ICL during S and G2 phases involves the Fanconi anemia pathway, with sensing of ICL by FANCM, and then recruitment of protein complex, resulting in ICL removal, creation of DSB, which is repaired by homologous recombination.

Figure 4

DNA double strand break repair. DSB are repaired by NHEJ or HRR pathways. NHEJ initiates with broken ends bound by Ku, which protects ends, leading to repair with partial resection and ligation of DNA ends. Alt-NHEJ is an alternative less accurate pathway. HRR is an accurate pathway. The DNA ends of the lesion are resected to allow invasion of the single strand into the sister chromatid used as a template for precise resynthesis of damaged DNA part. SSA is used only when two homologous regions flank the DSB site and is inaccurate.