Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination–deficient cancer models

Mehibel, Manal; Xu, Yu; Li, Caiyun G.; Moon, Eui Jung; Thakkar, Kaushik N.; Diep, Anh Nguyet; Kim, Ryan K.; Bloomstein, Joshua; Xiao, Yiren; Bacal, Julien; Saldivar, Joshua C.; Le, Quynh Thu; Cimprich, Karlene A.; Rankin, Erinn B.; Giaccia, Amato J.

doi:10.1172/jci146256

Cited by 25 publications

(19 citation statements)

References 67 publications

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“…In some instances, hypoxic tumor regions, which commonly occur in solid tumors, show decreased expression of HR proteins and increased sensitivity to chemotherapy [104,105]. However, the relationship between hypoxia and HR proficiency is dynamic, as severe hypoxia is associated with sensitivity to PARPi, while moderate hypoxia is associated with resistance [106].…”

Section: Extrinsic Determinants Of Hrdmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Cancers

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Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

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Section: Extrinsic Determinants Of Hrdmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Cancers

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“…As an example, it has been demonstrated in prostate and non-small cell lung cancer cell lines that the PARP inhibitor ABT-888 radiosensitised hypoxic (0.2% oxygen) tumour cells, but which was similar to that observed in normoxic tumour cells [ 89 ]. However, caution should be taken as recently it has been found that mild hypoxia (2% oxygen) actually increased the resistance of HR-proficient and deficient cancer cells to PARP inhibition, whilst severe hypoxic conditions (<0.5% oxygen) increased sensitivity [ 90 ]. Nevertheless, it is clear that more substantial research into DDR inhibition of hypoxic cells is needed to examine the potential for successful tumour radiosensitisation.…”

Section: Overcoming Hypoxic Radioresistance In Hnsccmentioning

confidence: 99%

Overcoming the Impact of Hypoxia in Driving Radiotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Hill

Rocha

Parsons

2022

Cancers

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Hypoxia is very common in most solid tumours and is a driving force for malignant progression as well as radiotherapy and chemotherapy resistance. Incidences of head and neck squamous cell carcinoma (HNSCC) have increased in the last decade and radiotherapy is a major therapeutic technique utilised in the treatment of the tumours. However, effectiveness of radiotherapy is hindered by resistance mechanisms and most notably by hypoxia, leading to poor patient prognosis of HNSCC patients. The phenomenon of hypoxia-induced radioresistance was identified nearly half a century ago, yet despite this, little progress has been made in overcoming the physical lack of oxygen. Therefore, a more detailed understanding of the molecular mechanisms of hypoxia and the underpinning radiobiological response of tumours to this phenotype is much needed. In this review, we will provide an up-to-date overview of how hypoxia alters molecular and cellular processes contributing to radioresistance, particularly in the context of HNSCC, and what strategies have and could be explored to overcome hypoxia-induced radioresistance.

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“…TPZ was also found to be capable of suppressing osteosarcoma cells under hypoxia in part through SLC7A11-mediated ferroptosis, which is a recently discovered type of cell death [130]. Interestingly, ferroptosis has been highlighted as a possible sensitiser of radioresistant cells [131]. Therefore, TPZ could be paired with ferroptosis inducers such as radiation and the ferroptosis inducer sulfasalazine [132].…”

Section: Tirapazaminementioning

confidence: 99%

Targeting Hypoxia: Revival of Old Remedies

2021

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Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression and aggressiveness. Despite the accumulative scientific and clinical efforts to target hypoxia, there is still a need to find specific treatments for tumour hypoxia. In this review, we discuss a variety of approaches to alter the low oxygen tumour microenvironment or hypoxia pathways including carbogen breathing, hyperthermia, hypoxia-activated prodrugs, tumour metabolism and hypoxia-inducible factor (HIF) inhibitors. The recent advances in technology and biological understanding reveal the importance of revisiting old therapeutic regimens and repurposing their uses clinically.

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Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination–deficient cancer models

Cited by 25 publications

References 67 publications

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Overcoming the Impact of Hypoxia in Driving Radiotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Targeting Hypoxia: Revival of Old Remedies

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