Preclinical studies of replication stress response inhibitors in DDR-defective hematologic malignancies
| Disease . | Phenotype . | Study . | Mode of targeting . | Drug combination . | Models . | Findings . |
|---|---|---|---|---|---|---|
| AML | FLT3-ITD | Yuan et al, 2014122 | CHK1 inhibition with SCH900776, UCN01, and CHIR124 | FLT3 inhibitor | Cell lines | AML proliferation is dependent on functional CHK1. CHK1 inhibitors reduce FLT3 activation |
| AML | Cytarabine resistance | Qi et al, 2014123 | CHK1 inhibition with LY2603618; WEE1 inhibition with MK-1775 | Cytarabine and roscovitine | Cell lines, primary tumor cells | AML cells exhibit dose-dependent sensitivity to CHK1 inhibitor that is CDK-dependent. CHK1 inhibitor synergizes with WEE1 inhibition. |
| AML | Cytarabine resistance | Di Tullio et al, 2017124 | CHK1 inhibition with GDC-0575 | Cytarabine | Cell lines, primary tumor cells, and PDX models | CHK1 inhibition increases in vitro and in vivo AML sensitivity to cytarabine, but does not affect hematopoiesis |
| AML | — | Ma et al, 2017125 | ATR inhibition with AZ20 and AZD6738 | Cytarabine | Cell lines, primary tumor cells | ATR inhibition abrogates the S and G2/M checkpoints and synergizes with cytarabine against AML cells |
| AML | — | Fordham et al, 2018126 | ATR inhibition with VX-970 | Gemcitabine and hydroxyurea | Orthotopic murine model | Antileukemic activity of hydroxyurea and gemcitabine is potentiated by ATR inhibition through abrogation of replication fork progression |
| AML | — | Qi et al, 2019127 | ATR inhibition with VE-821; Wee1 inhibition with AZD1775 | — | Cell lines | Combined ATR and WEE1 inhibition synergistically increases replication stress and DNA damage and induces apoptosis in AML cells |
| AML | MLL-ENL | Morgado-Palacin et al, 2016128 | ATM inhibition with AZD0156 ATR inhibition with AZ20 | — | N-RAS–driven MLL-ENL mouse model | ATR and ATM inhibition suppresses MLL-driven leukemias independently of p53 function |
| CML | BCR-ABL T315I | Lei et al, 2018129 | CHK1 inhibition with AZD7762 and MK-8776 | Imatinib | Cell lines, primary tumor cells, and cell line xenograft models | CHK1 inhibitors can overcome imatinib resistance in BCR-ABL T315I-mutant CML cells through CHIP–dependent degradation of BCR-ABL |
| ALL | — | Ghelli Luserni Di Rorà et al, 2021130 | CHK1 inhibition with prexasertib; ATR inhibition with VE-821 | Doxorubicin | Cell lines, primary tumor cells | ATR/CHK1 inhibitors potentiates doxorubicin–induced cytotoxicity in ALL |
| B-ALL | Mll-Af4/N-RasG12D | Chu et al, 2018131 | ATR inhibition with AZ20 | MEK inhibitors PD901 and trametinib | Transgenic and PDX mouse models | Combined MEK/ATR inhibition is effective against Mll-Af4/N-RasG12D B-ALL |
| T-ALL | — | Le et al, 2017132 | ATR inhibition with VE-822 | CDK inhibitor palbociclib | Cell lines, transgenic murine model | ATR inhibition abrogates nucleotide synthesis in T-ALL by suppressing ribonucleotide reductase and deoxycytidine kinase activity |
| CLL | ATM/TP53 mut/del | Kwok et al, 2016133 | ATR inhibition with ADZ6738 | Chemotherapy, ibrutinib | Cell lines, primary tumor cells | Defective ATM or p53 increases reliance on ATR-dependent regulation of replication stress in CLL |
| DLBCL | — | De Jong et al, 2020134 | WEE1 inhibition with AZD1775 | CHOP, radiotherapy | Cell lines | Combination of AZD1775 with radiotherapy or CHOP enhances sensitivity of DLBCL cells to WEE1 inhibition through unscheduled G2/M progression and increased DNA damage |
| Myc-driven lymphoma | Eμ-Myc+; ARF−/− | Murga et al, 201140 | ATR inhibition with ETP46464; CHK1 inhibition with SB-218078 | — | Murine models with defined levels of ATR signaling | The threshold of ATR signaling determines tumor outcome. ATR inhibition is tumor-suppressive in early tumorigenesis but is tumor promoting at later stages. |
| MM | Chromosome instability | Cottini et al, 2015135 | ATR inhibition with VE-821 | ROS inducer piperlongumine | Cell lines, primary tumor cells | MYC drives replicative and oxidative stress in MM. ATR inhibitor synergizes with piperlongumine. |
| MM | — | Xing et al, 2020136 | ATR inhibition with AZD6738; WEE1 inhibition with AZD1775; ATM inhibition with AZD0156 | Antibody-drug conjugate with DNA crosslinker | Cell lines, primary tumor cells, cell line xenograft models | Antibody-drug conjugate-induced DNA damage is synergistic with replication stress response inhibitors in MM |
| MM | Upregulation of p38/MK2 | Guo, 2019;137, Gu, 2021;138 Dietlein et al, 2016139 | MK2 knock out; MK2 inhibition with PF3644022 | Bortezomib, doxorubicin, dexamethasone, and Chk1 inhibitor | Cell lines, Transgenic models | MK2 is upregulated in high-risk MM and confers chemoresistance. Targeting MK2 induces MM killing in vitro and in vivo. MK2 and Chk1 inhibition are synthetically lethal in KRAS-mutant cancer cells. |
| Disease . | Phenotype . | Study . | Mode of targeting . | Drug combination . | Models . | Findings . |
|---|---|---|---|---|---|---|
| AML | FLT3-ITD | Yuan et al, 2014122 | CHK1 inhibition with SCH900776, UCN01, and CHIR124 | FLT3 inhibitor | Cell lines | AML proliferation is dependent on functional CHK1. CHK1 inhibitors reduce FLT3 activation |
| AML | Cytarabine resistance | Qi et al, 2014123 | CHK1 inhibition with LY2603618; WEE1 inhibition with MK-1775 | Cytarabine and roscovitine | Cell lines, primary tumor cells | AML cells exhibit dose-dependent sensitivity to CHK1 inhibitor that is CDK-dependent. CHK1 inhibitor synergizes with WEE1 inhibition. |
| AML | Cytarabine resistance | Di Tullio et al, 2017124 | CHK1 inhibition with GDC-0575 | Cytarabine | Cell lines, primary tumor cells, and PDX models | CHK1 inhibition increases in vitro and in vivo AML sensitivity to cytarabine, but does not affect hematopoiesis |
| AML | — | Ma et al, 2017125 | ATR inhibition with AZ20 and AZD6738 | Cytarabine | Cell lines, primary tumor cells | ATR inhibition abrogates the S and G2/M checkpoints and synergizes with cytarabine against AML cells |
| AML | — | Fordham et al, 2018126 | ATR inhibition with VX-970 | Gemcitabine and hydroxyurea | Orthotopic murine model | Antileukemic activity of hydroxyurea and gemcitabine is potentiated by ATR inhibition through abrogation of replication fork progression |
| AML | — | Qi et al, 2019127 | ATR inhibition with VE-821; Wee1 inhibition with AZD1775 | — | Cell lines | Combined ATR and WEE1 inhibition synergistically increases replication stress and DNA damage and induces apoptosis in AML cells |
| AML | MLL-ENL | Morgado-Palacin et al, 2016128 | ATM inhibition with AZD0156 ATR inhibition with AZ20 | — | N-RAS–driven MLL-ENL mouse model | ATR and ATM inhibition suppresses MLL-driven leukemias independently of p53 function |
| CML | BCR-ABL T315I | Lei et al, 2018129 | CHK1 inhibition with AZD7762 and MK-8776 | Imatinib | Cell lines, primary tumor cells, and cell line xenograft models | CHK1 inhibitors can overcome imatinib resistance in BCR-ABL T315I-mutant CML cells through CHIP–dependent degradation of BCR-ABL |
| ALL | — | Ghelli Luserni Di Rorà et al, 2021130 | CHK1 inhibition with prexasertib; ATR inhibition with VE-821 | Doxorubicin | Cell lines, primary tumor cells | ATR/CHK1 inhibitors potentiates doxorubicin–induced cytotoxicity in ALL |
| B-ALL | Mll-Af4/N-RasG12D | Chu et al, 2018131 | ATR inhibition with AZ20 | MEK inhibitors PD901 and trametinib | Transgenic and PDX mouse models | Combined MEK/ATR inhibition is effective against Mll-Af4/N-RasG12D B-ALL |
| T-ALL | — | Le et al, 2017132 | ATR inhibition with VE-822 | CDK inhibitor palbociclib | Cell lines, transgenic murine model | ATR inhibition abrogates nucleotide synthesis in T-ALL by suppressing ribonucleotide reductase and deoxycytidine kinase activity |
| CLL | ATM/TP53 mut/del | Kwok et al, 2016133 | ATR inhibition with ADZ6738 | Chemotherapy, ibrutinib | Cell lines, primary tumor cells | Defective ATM or p53 increases reliance on ATR-dependent regulation of replication stress in CLL |
| DLBCL | — | De Jong et al, 2020134 | WEE1 inhibition with AZD1775 | CHOP, radiotherapy | Cell lines | Combination of AZD1775 with radiotherapy or CHOP enhances sensitivity of DLBCL cells to WEE1 inhibition through unscheduled G2/M progression and increased DNA damage |
| Myc-driven lymphoma | Eμ-Myc+; ARF−/− | Murga et al, 201140 | ATR inhibition with ETP46464; CHK1 inhibition with SB-218078 | — | Murine models with defined levels of ATR signaling | The threshold of ATR signaling determines tumor outcome. ATR inhibition is tumor-suppressive in early tumorigenesis but is tumor promoting at later stages. |
| MM | Chromosome instability | Cottini et al, 2015135 | ATR inhibition with VE-821 | ROS inducer piperlongumine | Cell lines, primary tumor cells | MYC drives replicative and oxidative stress in MM. ATR inhibitor synergizes with piperlongumine. |
| MM | — | Xing et al, 2020136 | ATR inhibition with AZD6738; WEE1 inhibition with AZD1775; ATM inhibition with AZD0156 | Antibody-drug conjugate with DNA crosslinker | Cell lines, primary tumor cells, cell line xenograft models | Antibody-drug conjugate-induced DNA damage is synergistic with replication stress response inhibitors in MM |
| MM | Upregulation of p38/MK2 | Guo, 2019;137, Gu, 2021;138 Dietlein et al, 2016139 | MK2 knock out; MK2 inhibition with PF3644022 | Bortezomib, doxorubicin, dexamethasone, and Chk1 inhibitor | Cell lines, Transgenic models | MK2 is upregulated in high-risk MM and confers chemoresistance. Targeting MK2 induces MM killing in vitro and in vivo. MK2 and Chk1 inhibition are synthetically lethal in KRAS-mutant cancer cells. |
ALL, acute lymphoblastic leukemia; B-ALL; B-cell acute lymphoblastic leukemia; CDK, cyclin-dependent kinase; CHIP, carboxyl terminus of the Hsc70-interacting protein; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; MEK, mitogen-activated protein kinase; MM, multiple myeloma; ROS, reactive oxygen species; PDX, patient–derived xenograft; T-ALL, T-cell acute lymphoblastic leukemia.