Targeting the ATM Kinase to Enhance the Efficacy of Radiotherapy and Outcomes for Cancer Patients

Abstract

Targeting the DNA damage response represents a promising approach to improve the efficacy of radiation therapy. One appealing target for this approach is the serine/threonine kinase ataxia telangiectasia mutated (ATM), which is activated by DNA double strand breaks to orchestrate the cellular response to ionizing radiation. Small-molecule inhibitors targeting ATM have entered clinical trials testing their safety in combination with radiation therapy or in combination with other DNA damaging agents. Here, we review biochemical, genetic, and cellular functional studies of ATM, phenotypes associated with germline and somatic cancer mutations in ATM in humans, and experiments in genetically engineered mouse models that support a rationale for investigating ATM inhibitors as radiosensitizers for cancer therapy. These data identify important synthetic lethal relationships, which suggest that ATM inhibitors may be particularly effective in tumors with defects in other nodes of the DNA damage response. The potential for ATM inhibition to improve immunotherapy responses in preclinical models represents another emerging area of research. We summarize ongoing clinical trials of ATM inhibitors with radiotherapy. We also discuss critical ongoing areas of investigation that include discovery of biomarkers that predict for radiosensitization by ATM inhibitors and identification of effective combinations of ATM inhibitors, radiation therapy, other DNA damage response-directed therapies, and/or immunotherapies.

Figure 1.. Germline and somatic variants of the ATM gene.

The protein domain structure of ATM is shown, including the HEAT-repeat domain, followed by a FRAP-ATM-TRAPP (FAT) domain, the PI3K-like kinase domain, the PIKK regulatory domain (PRD), and a FAT C-terminal domain (FATC). A. Germline missense and out-of-frame frameshift variants causing truncating alterations, missense mutations, fusions, and in-frame frameshifts in ATM found in A-T patients (reported in ). B. Similarly, somatic cancer-derived variants from all ATM mutations identified in cancer in www.tumorportal.org are shown . Germline ATM variants tend to be truncating alterations, while missense alterations are more common among the somatic cancer mutations.

Figure 2.. ATM molecular pathway, with clinically available drugs identified.

Key nodes in the ATM pathway are shown. ATM is recruited to DSBs by the MRE11/RAD50/NBS1 complex. To activate, ATM transitions from an inactive dimer to a catalytically active monomer. ATM then phosphorylates downstream targets, including Chk1, Chk2, p53, and KAP1. ATR and DNA-PKcs are homologous PI3K kinases that regulate partially overlapping arms of the DDR, chiefly responding to DNA single strand breaks and mediating NHEJ to DSBs respectively.

Figure 3.. Proposed mechanisms by which ATM regulates innate immune responses.

ATM plays a critical role in signal transduction to promote DNA repair after the induction of DSBs by IR and other DNA damaging agents. When ATM is inactivated by genetic deletion or pharmacologic inhibition, damaged DNA is not properly repaired and can be released into the cytosol. Cytosolic DNA can be detected by cGAS, which signals to STING via the second messenger cGAMP. This leads to further signal transduction cascades that elicit transcription of type I interferon genes. Type I interferon expression then leads to T cell recruitment, antigen presentation processes, and local myeloid cell activation. By recruiting T cells to a tumor, stimulating these innate immune processes may increase the efficacy of immune checkpoint blockade therapies, such as anti-PD1 therapy. ATM depletion may also upregulate type I interferon gene expression via STING-independent pathways, shown on the right.