ATR inhibitors are a class of targeted therapy drugs currently being explored in cancer treatment. They function by blocking a specific protein within cells that plays a part in the cell’s internal repair mechanisms. This approach aims to hinder cancer cells’ ability to recover from damage, limiting their growth and survival.
The Role of ATR in Cell Health and DNA Repair
The ATR protein, short for Ataxia Telangiectasia and Rad3-related, monitors the integrity of the cell’s genetic material. It is a central component of the DNA Damage Response (DDR) system, a network of pathways that detect and repair DNA lesions. When DNA experiences stress, such as during replication or from environmental factors, single-stranded DNA (ssDNA) regions can form.
ATR recognizes these ssDNA structures, which often occur at stalled replication forks. This recognition triggers a cascade of events, including the phosphorylation of hundreds of substrates, notably the downstream kinase CHK1. Activating ATR leads to a temporary pause in the cell cycle, allowing time for DNA repair processes to be initiated and completed. This system is fundamental for maintaining genomic stability and preventing damaged cells from replicating, preserving the health and function of normal cells.
How ATR Inhibitors Target Cancer Cells
ATR inhibitors target a vulnerability often found in cancer cells. Many cancer cells possess defects in other DNA repair pathways, such as those involving the ATM protein or the TP53 tumor suppressor. These deficiencies mean that cancer cells become reliant on the ATR pathway to manage their DNA damage and survive. This reliance establishes a condition known as “synthetic lethality.”
Synthetic lethality describes a scenario where the loss of function in one pathway is not lethal on its own, but combined with the loss of another specific pathway, it results in cell death. Healthy cells, with intact ATM and TP53 pathways, can tolerate ATR inhibition. However, cancer cells that have lost ATM or TP53 function become dependent on ATR for survival. Blocking ATR in these compromised cancer cells leads to overwhelming DNA damage, replication fork collapse, and cell death, while largely sparing normal cells. This selective targeting exploits the genetic weaknesses of tumor cells.
Clinical Applications and Targeted Cancers
ATR inhibitors are undergoing investigation in clinical trials for various cancers. These include solid tumors such as ovarian, small-cell lung (SCLC), and gastrointestinal cancers, where DNA repair defects are common. Patients with tumors harboring genetic mutations, particularly in genes like ATM or TP53, are considered for these treatments due to their susceptibility to ATR inhibition. For example, ATM-deficient mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) cells are sensitive to ATR inhibitors.
Several ATR inhibitor drugs are being evaluated in clinical trials. Examples include Ceralasertib (AZD6738), Berzosertib (M6620/VX-970), Elimusertib (BAY1895344), Gartisertib (M4344), Camonsertib (RP-3500), and Tuvusertib (M1774). These agents are being tested as standalone therapies or in combination with other treatments. The focus remains on identifying which tumor types and genetic profiles respond best to ATR inhibition, advancing precision medicine in cancer care.
Enhancing Traditional Cancer Treatments
ATR inhibitors can enhance the effectiveness of traditional cancer therapies. Standard treatments like chemotherapy and radiation therapy damage cancer cells. However, cancer cells often develop resistance by activating their DNA repair mechanisms, including the ATR pathway, to mend the damage and survive.
Introducing an ATR inhibitor alongside conventional treatments prevents cancer cells from repairing induced DNA damage. This synergy makes cancer cells more sensitive to chemotherapy agents like cisplatin, carboplatin, or gemcitabine, and radiation. Disabling ATR-mediated repair can lead to increased cell death and overcome treatment resistance, improving outcomes. ATR inhibitors are also explored in combination with other targeted therapies, such as PARP inhibitors. PARP inhibitors cause single-strand breaks that can progress into double-strand breaks, which activate ATR, making combined inhibition a strong strategy against certain cancers.