Therapeutic inhibition of ATR in differentiated thyroid cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Ataxia telangiectasia and Rad3-related protein (ATR) is crucial for DNA damage response and a cancer treatment target.
• Differentiated thyroid cancer (DTC) remains a significant clinical challenge, necessitating novel therapeutic strategies.

Purpose of the Study:

• To evaluate the efficacy of the ATR inhibitor BAY 1895344 as a potential therapy for differentiated thyroid cancer (DTC).
• To assess the synergistic effects of BAY 1895344 in combination with established DTC treatments.

Main Methods:

• In vitro studies using four DTC cell lines (TPC1, K1, FTC-133, FTC-238) to assess cell viability, cell cycle arrest, apoptosis, and caspase-3 activity.
• In vivo xenograft models using K1 and FTC-133 cell lines to evaluate tumor growth inhibition.
• Combination studies with sorafenib, lenvatinib, dabrafenib, and trametinib.

Main Results:

• BAY 1895344 inhibited DTC cell viability and induced G2/M phase arrest, apoptosis, and increased caspase-3 activity.
• Combination therapies, particularly BAY 1895344 with lenvatinib or dabrafenib plus trametinib (in BRAFV600E-mutated cells), demonstrated synergistic effects.
• BAY 1895344 monotherapy and combination treatments showed significant tumor growth retardation in xenograft models with no apparent toxicity.

Conclusions:

• BAY 1895344 exhibits potent anti-cancer activity in DTC models, both as a single agent and in combination therapies.
• These findings support the clinical development of BAY 1895344 for differentiated thyroid cancer treatment.