Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint

Abstract

Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here we report that A3A is highly expressed in subsets of pediatric and adult acute myeloid leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy.

Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma

“…In fact, recent studies implicated that inhibition of DNA damage response (e.g., inhibition of PARP and ATR) in cells with high APOBEC expression promoted apoptosis and cell death. 41 , 42 Meanwhile, inhibiting APOBEC expression led to prolonged tamoxifen responses for ER + breast cancer in murine xenografts. 20 On the other hand, APOBEC signature was associated with high mutation burden and a large number of neoantigens may be generated due to APOBEC mutagenic effect.…”

Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

“…In addition to sublethal APOBEC mutagenesis driving tumour heterogeneity, APOBEC has recently also been shown to produce replication stress in cancer [ 65 , 71 , 72 ]. This complements our previous observation that replication stress itself can drive A3B expression and activity [ 73 ], which suggests a positive feedforward loop involving replication stress and APOBEC mutagenesis (Figure 5 ).…”

“…The first strategy is therapy by hypermutation, by enhancing the mutagenic effects of APOBEC to the point where cancer cells suffer catastrophic levels of DNA damage and selectively die. Indeed, recent studies have suggested that DDR inhibitors, such as PARP and ATR inhibitors, may sensitize tumour cells with high levels of APOBEC to an APOBEC-dependent death [ 65 , 71 , 72 ].…”

A consensus set of genetic vulnerabilities to ATR inhibition

“…These critical functions of ATR in coordinating the response to replication stress has made it an attractive therapeutic target in oncology given the observation that tumors often display signs of replication stress (Gaillard et al 2015;Lecona and Fernandez-Capetillo 2018 (Reaper et al 2011;Morgado-Palacin et al 2016;Nieto-Soler et al 2016;Williamson et al 2016;Buisson et al 2017;Green et al 2017;Jones et al 2017). Hustedt al., We reasoned that the unbiased identification of genes promoting viability following ATR inhibition would be useful for two purposes.…”