TY - JOUR
T1 - Associating drug sensitivity with differentiation status identifies effective combinations for acute myeloid leukemia
AU - Kurtz, Stephen E.
AU - Eide, Christopher A.
AU - Kaempf, Andy
AU - Long, Nicola
AU - Bottomly, Daniel
AU - Nikolova, Olga
AU - Druker, Brian J.
AU - McWeeney, Shannon K.
AU - Chang, Bill H.
AU - Tyner, Jeffrey W.
AU - Agarwal, Anupriya
N1 - Funding Information:
This work was supported by the Drug Sensitivity and Resistance Network, National Institutes of Health (NIH), National Cancer Institute (NCI) grant U54CA224019, and the Cancer Target Discovery and Development Network grant U01CA217862. This work was additionally supported by the V Foundation for Cancer Research (J.W.T.), the Gabrielle’s Angel Foundation for Cancer Research (J.W.T.), the Anna Fuller Fund (J.W.T.), the Mark Foundation for Cancer Research (J.W.T.), and the Silver Family Foundation (J.W.T.), by grants from the NCI grant R01CA229875-01A1 (A.A.), National Heart, Lung, and Blood Institute grant R01HL155426-01 (A.A.), American Cancer Society RSG-17-187-01-LIB (A.A.), Alex Lemonade/Babich RUNX1 Foundation (A.A.), EvansMDS Foundation (A.A.), and a V Foundation Scholar award (A.A.).
Funding Information:
Conflict-of-interest disclosure: B.J.D. serves on scientific advisory boards for Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, Novartis, Gilead Sciences (inactive), Monojul (inactive); serves on Scientific Advisory Board and receives stock from Aptose Biosciences, Blueprint Medicines, EnLiven Therapeutics, Iterion Therapeutics, Third Coast Therapeutics, GRAIL (inactive on scientific advisory board); is scientific founder of MolecularMD (inactive, acquired by ICON); serves on the board of directors and receives stock from Amgen, Vincera Pharma; serves on the board of directors for Burroughs Wellcome Fund, CureOne; serves on the joint steering committee for Beat AML LLS; is founder of VB Therapeutics; has a sponsored research agreement with EnLiven Therapeutics; receives clinical trial funding from Novartis, Bristol-Myers Squibb, Pfizer. J.W.T. receives research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Jans-sen, Petra, Seattle Genetics, Syros, Tolero, and Takeda. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2022 by The American Society of Hematology.
PY - 2022/5/24
Y1 - 2022/5/24
N2 - Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared with each single agent across 335 acute myeloid leukemia (AML) patient samples while sparing primary stromal cells. Single-agent DORA and VEN sensitivity was associated with distinct, nonoverlapping tumor cell differentiation states. In particular, increased monocytes, M4/M5 French-American-British classification, and CD141 immunophenotype tracked with sensitivity to DORA and resistance to VEN but were mitigated with the combination. Increased expression of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were observed in monocytic and undifferentiated leukemias, respectively. Enrichment for DORA and VEN sensitivities was observed in AML with monocyte-like and progenitor-like transcriptomic signatures, respectively, and these associations diminished with the combination. The mechanism underlying the combination’s enhanced efficacy may result from inhibition of p38 MAPK-mediated phosphorylation of BCL2, which in turn enhances sensitivity to VEN. These findings suggest exploiting complementary drug sensitivity profiles with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML.
AB - Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared with each single agent across 335 acute myeloid leukemia (AML) patient samples while sparing primary stromal cells. Single-agent DORA and VEN sensitivity was associated with distinct, nonoverlapping tumor cell differentiation states. In particular, increased monocytes, M4/M5 French-American-British classification, and CD141 immunophenotype tracked with sensitivity to DORA and resistance to VEN but were mitigated with the combination. Increased expression of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were observed in monocytic and undifferentiated leukemias, respectively. Enrichment for DORA and VEN sensitivities was observed in AML with monocyte-like and progenitor-like transcriptomic signatures, respectively, and these associations diminished with the combination. The mechanism underlying the combination’s enhanced efficacy may result from inhibition of p38 MAPK-mediated phosphorylation of BCL2, which in turn enhances sensitivity to VEN. These findings suggest exploiting complementary drug sensitivity profiles with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML.
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U2 - 10.1182/bloodadvances.2021006307
DO - 10.1182/bloodadvances.2021006307
M3 - Article
C2 - 35078224
AN - SCOPUS:85130475449
SN - 2473-9529
VL - 6
SP - 3062
EP - 3067
JO - Blood Advances
JF - Blood Advances
IS - 10
ER -