“Contextual” Synthetic Lethality and/or Loss of Heterozygosity: Tumor Hypoxia and Modification of DNA Repair

Abstract

Hypoxia exists in every solid tumor and is associated with poor prognosis because of both local and systemic therapeutic resistance. Recent studies have focused on the interaction between tumor cell genetics and the dynamic state of oxygenation and metabolism. Hypoxia generates aggressive tumor cell phenotypes in part owing to ongoing genetic instability and a "mutator" phenotype. The latter may be due to suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and double-strand break (DSB) repair. We propose a theoretical model in which hypoxia-mediated defects in DNA repair can lead to "contextual loss of heterozygosity" and drive oncogenesis. Additionally, hypoxia-mediated repair defects can be specifically targeted by DNA damaging agents and/or "contextual synthetic lethality" to kill repair-deficient cells and preserve the therapeutic ratio. These proposed concepts support the interrogation of solid tumors to document repair defects in both oxic and hypoxic tumor subregions as a conduit to novel clinical trials within the context of personalized medicine. Clin Cancer Res; 16(18); 4553-60. ©2010 AACR.The microenvironment of solid tumors differs greatly from that of normal tissues as it can contain regions of hypoxia (a decreased level of oxygen), increased interstitial fluid pressure, and decreased pH and nutrient delivery (1, 2). Hypoxia is associated with both local and systemic therapy resistance, and decreased disease-free survival has been observed in many human cancers (3-11). Importantly, hypoxia is an adverse prognostic factor in cancers treated with either radiotherapy or surgery. Hence hypoxia is not only a determinant of local radio-or chemoresistance, but also tumor progression and systemic metastasis. The latter may be due to altered transcription and translation of metastatic genes, but could also be secondary to clonal selection of a "mutator" phenotype (12,13). This unstable phenotype may result from hypoxia-mediated suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and doublestrand break (DSB) repair [whether by homologous recombination (HR) or nonhomologous end-joining (NHEJ)]. Suppression of DNA repair in oxic and hypoxic cells may, therefore, have profound consequences, given that residual or misrepaired DNA breaks can be highly carcinogenic and generate chromosomal alterations in oncogenes and tumor suppressor genes during tumor progression (14,15).This report critically reviews preclinical and clinical studies that link tumor hypoxia and DNA repair pathways as drivers of genetic instability and tumor progression. We also highlight recent work in which these DNA repair defects in aggressive cancer cells can be exploited with novel therapeutic approaches. Models of Hypoxia and Resistance to Radiotherapy and ChemotherapyThe abnormal vasculature of tumors resulting from unregulated angiogenesis is probably the most important contributor to the development of both chronic and acute hypoxia in the majority of solid tumors (reviewed in ref. ...

RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break–Inducing Anticancer Drugs

“…6G). Our findings are in sharp contrast to those of Chan and Bristow (24), who showed that Ku70 was downregulated under hypoxia, which, in turn, led to a decrease in NHEJ repair (24).…”

“…In addition, tumor hypoxia is a driving force of genetic instability and is pivotal in cancer development and chemoresistance (1,(21)(22)(23). Hypoxic cancer cells usually exhibit dysregulated DNA repair (24)(25)(26), but data conflict about the functional status of the NHEJ repair pathway under hypoxia (27)(28)(29). The molecular basis of DNA repair-mediated chemoresistance under hypoxia thus deserves further investigation.…”

Chronic hypoxia compromises repair of DNA double-strand breaks to drive genetic instability

“…An understanding of DNA-dsb repair defects in hypoxic cells could help target hypoxia-induced resistance within human tumors to improve current cancer treatment modalities. Indeed, we recently reported that hypoxic cells are more sensitive to PARP inhibitors in vivo and suggest that genetic instability in hypoxic cells could be offset by these contextual synthetic lethality approaches (Chan and Bristow, 2010;.…”

An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy

“…72,75 We have shown in principle that PARP1 inhibition can preferentially kill repair-defective hypoxic tumour clonogens, while sparing normal tissues that maintain their DNA repair capability. Other contextual synthetic lethal approaches could be the inhibition of DNA polymerase-b in MMR-deficient hypoxic cells or inhibition of the ataxia telangiectasia mutated (ATM) kinase in hypoxic cells that have defective FA pathway function.…”

“…Other contextual synthetic lethal approaches could be the inhibition of DNA polymerase-b in MMR-deficient hypoxic cells or inhibition of the ataxia telangiectasia mutated (ATM) kinase in hypoxic cells that have defective FA pathway function. 8,75,76 Of interest, clinicians may already be combatting genetic instability and hypoxia in CaP with the combined use of ADT and RT. 8 This combination has led to improved overall and CaPspecific survival in high-risk and locally advanced CaP.…”