Enhancing radiosensitivity: Targeting the DNA repair pathways

Abstract

Radiotherapy is very effective in local control of cancerous tumors, but its curative potential is often limited by intrinsic radioresistance of the tumor cells. Since DNA repair pathways remove radiation-induced DNA lesions and protect cells from lethality, these pathways represent potential therapeutic targets to radiosensitize tumors. In order to achieve a therapeutic gain, however, there must be a differential between tumor and normal cells that can be exploited to preferentially target the DNA repair of the tumor, while sparing surrounding normal tissues, and this has represented a significant challenge to progress. Nevertheless, recent advances in our understanding of DNA repair mechanisms and tumor biology, on both the biochemical and genetic levels, have identified molecular differentials that may increase tumor specificity. This mechanistic insight suggests new strategies for radiotherapeutic targeting of DNA repair. Some of these strategies are reviewed here, including synthetic lethal, replicative stress, cell cycle and hypoxia-based approaches. The example of PARP1 inhibitor use in BRCA1 and 2 mutated breast cancer therapy is discussed, and future directions and challenges are explored.

Genetic polymorphisms in XRCC1 associated with radiation therapy in prostate cancer

“…Multiple DNA repair pathways are involved to maintain the genomic integrity, and the homologous recombination (HR) and non-homologous end-joining (NHEJ), nucleotide excision repair (NER) and base excision repair (BER) pathways are thought to contribute heavily to remove the damage caused by ionizing radiation. 4,5 XRCC1 was the first human gene cloned in the BER pathway, and cells lacking this gene product are hypersensitive to ionizing radiation.…”

“…3 The types of DNA damage induced by radiation include DNA base damage and both single-and double-strand DNA breaks. 4 Such lesions, if inadequately repaired, can lead to cell death by lethal chromosomal aberrations or apoptosis, the desired Radiation therapy is a potentially curative, important treatment option in localized prostate cancer. However, at 8 years after radiation therapy, even in the best risk subset of patients, approximately 10% of patients will experience clinical disease recurrence.…”

Synthetic lethality: exploiting the addiction of cancer to DNA repair

“…One other possible long-term adverse result from this mechanism is that inhibiting DNA repair in normal tissues may increase the risk of secondary malignancies from this type of therapy. 89 Second, many cancers do not depend on a single DNA repair pathway to overcome a defect in another pathway. Third, the tumor specificity of many DNA repair components is not well defined.…”

Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy

“…Hence, it is possible that gene expression correlated with TRG might reflect the characteristics, including resistance to CRT, of residual cancer cells and might be associated with prognosis in patients with rectal cancer after pre-operative CRT. DNA repair pathways (9), cell cycle pathways (10), hypoxia (11,12), anti-apoptosis (13) and cancer stem cells (14,15) have been implicated in the mechanisms of CRT resistance. Twenty genes were selected for a comparison in expression levels between CRT responders and non-responders: PCNA and MKI67 (Ki67) as proliferative markers; CDKN1A (p21…”