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A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM
Daniel L Menezes1, Jenny Holt2, Yan Tang2
1Novartis Institutes for BioMedical Research, Emeryville, California. lorenataricani@yahoo.com dmenezes1@gmail.com.
Unlabelled:
Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost.
Implications:
These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited.
Insights
Targeting ATR with inhibitors shows therapeutic promise for cancers with ATM loss. This approach leverages synthetic lethality to selectively kill cancer cells by impairing DNA repair mechanisms.
Area of Science:
- Genomic stability and DNA damage response pathways.
- Cancer cell biology and therapeutic strategies.
Background:
- Genomic integrity is crucial for cell viability; disruptions in DNA damage response (DDR) factors like ATM and ATR compromise this integrity.
- Cancers with ATM mutations often have impaired DNA double-strand break (DSB) repair, relying on compensatory mechanisms for survival.
Purpose of the Study:
- To identify novel synthetic lethal partners of ATR inhibitors (ATRi) using siRNA screening.
- To evaluate the therapeutic potential of ATR inhibition in ATM-deficient cancers.
Main Methods:
- A high-content γ-H2AX assay was employed for a synthetic lethal siRNA screen.
- In vitro and in vivo models, including ATM-deficient mantle cell lymphoma (MCL), were used to assess ATR inhibition efficacy.
Main Results:
- The screen confirmed ATM and identified other replication checkpoint proteins that enhance ATRi response when ablated.
- ATR inhibition in ATM-deficient contexts induced DNA-PKcs phosphorylation and γ-H2AX, leading to enhanced efficacy in ATM loss-of-function MCL models compared to ATM wild-type cells.
Conclusions:
- Single-agent ATR inhibitors demonstrate therapeutic utility in ATM-deficient cancers, such as MCL.
- ATR plays a role in maintaining genomic stability through a complex network of proteins, presenting opportunities for further therapeutic exploitation.
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