Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• TRAIL death receptor agonists combined with radiochemotherapy are investigated for advanced cancers.
• Normal cells with functional DNA damage response (DDR) upregulate DR5 in a p53-dependent manner, sensitizing them to DR5 agonists.
• The selective sensitization of cancer cells versus normal tissues by DR5 agonists post-chemotherapy is not fully understood.

Purpose of the Study:

• To investigate the selective sensitization of cancer cells versus normal tissues by DR5 agonists after DNA-damaging chemotherapy.
• To determine the extent to which normal tissues are targeted in combination therapies.
• To explore potential strategies to mitigate treatment-related toxicities.

Main Methods:

• Administration of DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wild-type mice.
• Assessment of gastrointestinal toxicities (GIT) and Lgr5(+) stem cell death.
• Treatment of normal human epithelial cells with DR5-agonistic mAb and chemotherapeutic agents.
• Genetic or pharmacologic targeting of Chk2 in combination therapy models.

Main Results:

• Combined DR5 agonist and chemotherapy administration induced synergistic GIT in mice.
• GIT was linked to p53- and DR5-dependent death of Lgr5(+) crypt base columnar stem cells.
• Normal human epithelial cells showed increased sensitization to cell death upon combined treatment.
• Targeting Chk2 potentially counteracted GIT without compromising antitumor responses.

Conclusions:

• Combination therapy with DR5-targeting agonistic mAbs and DNA-damaging chemotherapy poses a risk of toxicity-induced conditions.
• The impact of mAb-based strategies on chemotherapy's dose-limiting toxicity requires careful consideration for new combination therapies.
• The DNA damage response (DDR) is linked to TRAIL death receptor signaling in normal cells, influencing treatment outcomes.