A19: ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53 or ATM defective chronic lymphocytic leukaemia cells

Marwan Kwok1,2,Nicholas Davies1,Angelo Agathaggelou1,Edward Smith1,Ceri Oldreive1,Eva Petermann1,Grant Stewart1,Jeff Brown3,Alan Lau4,Guy Pratt1,5,Helen Parry1,2,Malcolm Taylor1,Paul Moss1,2,Peter Hillmen6,Tatjana Stankovic1,2

1School of Cancer Sciences, University of Birmingham, Birmingham, UK,2Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, UK,3Oncology iMed, AstraZeneca Pharmaceuticals, Waltham, USA,4R&D Oncology iMed, AstraZeneca Pharmaceuticals, Alderley Park, UK,5Birmingham Heartlands Hospital, Birmingham, UK,6Leeds Institute of Cancer & Pathology, University of Leeds, Leeds, UK

Presenting date: Monday 2 November
Presenting time: 12.20-13.10


TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability and chemoresistance in chronic lymphocytic leukaemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53 or ATM defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled forks into chromatid fragments that require resolution through the ATM/p53 pathway. This is the first study to address synthetic lethality between TP53/ATM functional loss and ATR inhibition in a haematological malignancy using primary tumour samples and in vivo models.


We performed in vitro and ex vivo analyses on CLL cell lines, primary CLL samples (n=34, with different genetic composition) and biallelic TP53 or ATM defective primary CLL xenografts (n=5) treated with AZD6738, a novel ATR kinase inhibitor, to determine its efficacy and cytotoxic mechanism.


Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53 or ATM defective CLL cells, inhibition of ATR signalling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis due to defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53 and ATM defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53 or ATM defective CLL, where treatment with AZD6738 resulted in decreased tumour load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitised TP53 or ATM defective primary CLL cells and xenografts to chemotherapy, and synergised with the B-cell signalling inhibitor ibrutinib.


Our findings suggest that ATR is a promising therapeutic target for TP53 or ATM defective CLL that warrants clinical investigation.