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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.
Abstract:
Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.
Insights
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.
