Download 582-595 February 4, 2016

ATR inhibition induces synthetic lethality and overcomes
chemoresistance in TP53- or ATM-defective chronic
lymphocytic leukemia cells
by Marwan Kwok, Nicholas Davies, Angelo Agathanggelou, Edward Smith, Ceri
Oldreive, Eva Petermann, Grant Stewart, Jeff Brown, Alan Lau, Guy Pratt, Helen
Parry, Malcolm Taylor, Paul Moss, Peter Hillmen, and Tatjana Stankovic
Blood
Volume 127(5):582-595
February 4, 2016
©2016 by American Society of Hematology
ATR signaling is activated in response to replication stress in proliferating primary CLL cells
and is inhibited by AZD6738.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
ATR inhibition is selectively cytotoxic to both ATM-defective and TP53-defective CLL cells in
vitro and in vivo.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
ATR inhibition leads to increased replication stress and ATM/p53 dependent G1/S cell cycle
arrest in CLL cells.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
ATR inhibition results in accumulation of DNA damage and mitotic catastrophe in CLL cells with
ATM or p53 deficiency.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
ATR inhibition sensitizes CII-ATMsh and Mec1 CLL cells to cytotoxic chemotherapy.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
ATR inhibition synergizes with existing therapeutic agents both in ATM-defective and TP53defective primary CLL cells.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology
A model for synthetic lethality in CLL cells with ATM or p53 deficiency by inhibition of ATR. ATM
and ATR are master regulators of DDR, with ATM being activated in response to DNA doublestrand breaks, and ATR in response to replication stress.
Marwan Kwok et al. Blood 2016;127:582-595
©2016 by American Society of Hematology