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Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.
Sonja J Gill1, Paul W G Wijnhoven2, Jacqueline H L Fok2
1Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
Molecular Cancer Therapeutics
|June 23, 2021
Summary
Combinations of radiotherapy with DNA damage response inhibitors (DDRi) can enhance cancer treatment. Lower DDRi concentrations are effective in combination therapy, potentially improving the therapeutic index, especially in DDR-deficient tumors.
Area of Science:
- Oncology
- Radiation Oncology
- Molecular Biology
- Pharmacology
Background:
- Radiotherapy is a cornerstone of cancer treatment.
- Combining radiotherapy with targeted agents is crucial for maximizing efficacy and minimizing normal tissue toxicity.
- DNA damage response inhibitors (DDRi) are a promising class of targeted agents for combination therapy.
Purpose of the Study:
- To evaluate the radiopotentiation profiles of five DDRi: olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK).
- To assess the influence of drug concentration and cellular DDR deficiencies on DDRi-mediated radiopotentiation.
- To identify optimal dosing strategies for DDRi in combination with radiotherapy to enhance the therapeutic index.
Main Methods:
- A radiotherapy combination screen was performed using six lung cancer cell lines with diverse genetic aberrations.
- Clonogenic assays were employed to assess the effects of multiple DDRi concentrations combined with a fixed radiotherapy dose.
- Radiosensitization was evaluated in relation to drug concentration and specific DDR deficiencies (e.g., TP53, ATM mutations).
Main Results:
- Effective concentrations of DDRi for radiosensitization were lower than those required for single-agent efficacy.
- Low concentrations of adavosertib (WEE1 inhibitor) preferentially sensitized p53-deficient lung cancer cells.
- Olaparib, ceralasertib, and adavosertib demonstrated a favorable safety profile with moderate dose enhancement increases.
- AZD0156 and KU-60648 showed steep increases in dose enhancement with small concentration increments.
Conclusions:
- Radiopotentiation profiling can guide the selection of effective DDRi doses and identify relevant biomarkers for radiosensitization.
- The study highlights the potential to increase the therapeutic index by exploiting DDR deficiencies with low-dose DDRi combinations.
- Multiple concentration testing provides critical insights into the drug concentration-radiotherapy effect relationship, informing future clinical trial dose-escalation strategies.
