Combining Targeted DNA Repair Inhibition and Immune-Oncology Approaches for Enhanced Tumor Control

Authors

Kyle Concannon
Benjamin B Morris
Carl M Gay
Lauren A Byers

Publication Date

3-2-2023

Journal

Molecular Cell

Abstract

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.

Keywords

DNA damage repair, Mismatch Repair Deficits, PARP, ATR, Immuno-Oncology, Immune Checkpoint Blockade, Biomarkers, STING, cGAS-STING, DDRi-IO, Cellular Therapy

Comments

PMID: 36669489

DOI

10.1016/j.molcel.2022.12.031

PMID

36669489

PMCID

PMC9992136

PubMedCentral® Posted Date

March 2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes