ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Metastatic clear cell renal cell carcinomas (ccRCCs) exhibit resistance to conventional DNA-damaging chemotherapies.
• Existing treatments like tyrosine kinase inhibitors and immune checkpoint therapies have limitations for resistant ccRCC.
• ccRCCs often present with high endogenous DNA damage but maintain intact DNA damage response pathways.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting the ataxia telangiectasia and Rad3-related protein (ATR) kinase in ccRCC.
• To evaluate the efficacy of M4344 (gartisertib), a selective ATR inhibitor, as a single agent and in combination therapy for ccRCC.

Main Methods:

• Pharmacological inhibition of ATR kinase using M4344 in ccRCC cell lines and xenograft models.
• Assessment of cellular responses to M4344, including proliferation, DNA damage accumulation, and cell cycle progression.
• Evaluation of M4344 in combination with cisplatin, carboplatin, and olaparib in preclinical ccRCC models.

Main Results:

• M4344 induced significant antiproliferative effects in ccRCC cells by causing replication stress and DNA damage during S phase.
• ATR inhibition led to persistent DNA damage, micronuclei formation, and G2/M and G1 phase arrest.
• Single-agent M4344 treatment inhibited ccRCC xenograft tumor growth.
• M4344 demonstrated synergistic effects with cisplatin, carboplatin, and olaparib in vitro and in vivo.

Conclusions:

• ATR inhibition represents a promising novel therapeutic strategy for metastatic clear cell renal cell carcinomas.
• M4344 shows efficacy as a single agent and synergizes with standard chemotherapeutic agents and PARP inhibitors.
• Targeting ATR offers a potential new avenue for treating patients with therapy-resistant ccRCC.