vx-970 and Colorectal-Neoplasms

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically "cold", emphasizing combination strategies to turn the "cold" tumor "hot" to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.. The efficacy of combining ATRi, IR, and anti-PD-L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co-immunoprecipitation, and real-time quantitative PCR in multiple murine and human CRC cell lines.. The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Colorectal Neoplasms; Humans; Immunotherapy; Mice; Pyrazines; Tumor Microenvironment

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Checkpoint Kinase 2; Colorectal Neoplasms; DNA Breaks, Double-Stranded; Drug Resistance, Neoplasm; Female; Humans; Isoxazoles; Mice, Inbred C57BL; Oxaliplatin; Pyrazines; T-Lymphocytes; Xenograft Model Antitumor Assays

The Chk1 and ATR kinases are critical mediators of the DNA damage response pathway and help protect cancer cells from endogenous and oncogene induced replication stress. Inhibitors of both kinases are currently being evaluated in clinical trials. Chk1 inhibition with V158411 increases DNA damage and activates the ATR, ATM and DNA-PKcs dependent DNA damage response pathways. Inhibiting ATR, ATM and/or DNA-PKcs has the potential to increase the therapeutic activity of Chk1 inhibitors. ATR inhibition but not ATM or DNA-PKcs inhibition potentiated the cytotoxicity of V158411 in p53 mutant and wild type human cancer cell lines. This increased cytotoxicity correlated with increased nuclear DNA damage and replication stress in a dose and time dependent manner. γH2AX induction following Chk1 inhibition protected cells from caspase-dependent apoptosis. Inhibition of ATR increased Chk1 inhibitor induced cell death independently of caspase activation. The effect of ATR, ATM and/or DNA-PK inhibition on Chk1 inhibitor induced replication stress was dependent on the concentration of Chk1 inhibitor. ATR inhibition potentiated Chk1 inhibitor induced replication stress and cytotoxicity via the abrogation of ATR-dependent feedback activation of Chk1 induced by Chk1 inhibitor generated replication stress. This study suggests that combining an ATR inhibitor to lower the threshold by which a Chk1 inhibitor induces replication stress, DNA damage and tumour cell death in a wide range of cancer types may be a useful clinical approach.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Bone Neoplasms; Cell Proliferation; Checkpoint Kinase 1; Colorectal Neoplasms; DNA Damage; DNA-Activated Protein Kinase; Dose-Response Relationship, Drug; Histones; HT29 Cells; Humans; Indoles; Isoxazoles; Molecular Targeted Therapy; Nuclear Proteins; Osteosarcoma; Protein Kinase Inhibitors; Pyrazines; Pyridones; Signal Transduction; Time Factors