TY - GEN
T1 - ATR Inhibition Exacerbates Replication Stress in TP53 or ATM Deficient CLL Cells and Enhances Sensitivity to Chemotherapy and Targeted Therapy
AU - Kwok, Marwan Cheng Kuang
AU - Davies, Nick
AU - Agathanggelou, Angelo
AU - Smith, Edward
AU - Petermann, Eva
AU - Yates, Eliot
AU - Brown, Jeffrey
AU - Lau, Alan
AU - Stankovic, Tatjana
PY - 2014/12/6
Y1 - 2014/12/6
N2 - DNA damage response (DDR) defects, particularly TP53 or biallelic ATM aberrations, are associated with chemoresistance in chronic lymphocytic leukemia (CLL). Chemoimmunotherapy or B-cell receptor signaling inhibitors alone may not be sufficient to overcome adverse prognosis or provide durable response in TP53 or biallelic ATM inactivated CLL. In particular, genomic instability resulting from impaired DDR facilitates rapid clonal evolution leading to treatment refractoriness or disease relapse. Development of therapeutic approaches specifically targeting DDR defects is therefore necessary for effective long-term control of DDR-defective CLL. We previously demonstrated selective cytotoxicity of the ATR inhibitor AZD6738 towards TP53 or ATM null CLL cells, and validated this in CLL xenograft models for biallelic TP53 or ATM loss. Here, we provide mechanistic insight into the synthetically lethal interactions between ATR pathway inhibition and TP53 or ATM loss in CLL, and offer experimental evidence supporting the use of ATR inhibition in combination with conventional chemotherapies and other targeted therapies in CLL.
AB - DNA damage response (DDR) defects, particularly TP53 or biallelic ATM aberrations, are associated with chemoresistance in chronic lymphocytic leukemia (CLL). Chemoimmunotherapy or B-cell receptor signaling inhibitors alone may not be sufficient to overcome adverse prognosis or provide durable response in TP53 or biallelic ATM inactivated CLL. In particular, genomic instability resulting from impaired DDR facilitates rapid clonal evolution leading to treatment refractoriness or disease relapse. Development of therapeutic approaches specifically targeting DDR defects is therefore necessary for effective long-term control of DDR-defective CLL. We previously demonstrated selective cytotoxicity of the ATR inhibitor AZD6738 towards TP53 or ATM null CLL cells, and validated this in CLL xenograft models for biallelic TP53 or ATM loss. Here, we provide mechanistic insight into the synthetically lethal interactions between ATR pathway inhibition and TP53 or ATM loss in CLL, and offer experimental evidence supporting the use of ATR inhibition in combination with conventional chemotherapies and other targeted therapies in CLL.
UR - http://dx.doi.org/10.1182/blood.v124.21.3340.3340
U2 - 10.1182/blood.v124.21.3340.3340
DO - 10.1182/blood.v124.21.3340.3340
M3 - Conference contribution
VL - 124
T3 - Blood
SP - 3340
BT - Blood
ER -