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Associating drug sensitivity with differentiation status identifies effective combinations for acute myeloid leukemia

Stephen E Kurtz1,2, Christopher A Eide1, Andy Kaempf3

  • 1Division of Hematology & Medical Oncology.

Blood Advances
|January 25, 2022
PubMed

Insights

Combining doramapimod (DORA), a p38 MAPK inhibitor, with venetoclax (VEN), a BCL2 inhibitor, shows enhanced efficacy in acute myeloid leukemia (AML) patient samples. This dual targeting strategy overcomes resistance and offers broad effectiveness across diverse AML subtypes.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) is characterized by significant cellular heterogeneity.
  • Existing treatments often face challenges due to diverse drug sensitivity profiles within AML subtypes.
  • Identifying novel therapeutic combinations is crucial for improving patient outcomes.

Purpose of the Study:

  • To evaluate the combined efficacy of doramapimod (DORA) and venetoclax (VEN) in ex vivo drug screening of primary AML patient samples.
  • To investigate the relationship between leukemic cell differentiation states and sensitivity to DORA and VEN.
  • To elucidate the potential mechanism of action for the observed enhanced efficacy of the combination therapy.

Main Methods:

  • Ex vivo drug screening of 335 primary AML patient samples using doramapimod (DORA) and venetoclax (VEN).
  • Analysis of drug sensitivity in relation to immunophenotype (CD14+), French-American-British classification (M4/M5), and transcriptomic signatures.
  • Assessment of target gene expression (MAPK14, BCL2) and potential drug interaction mechanisms.

Main Results:

  • The combination of DORA and VEN demonstrated broad, enhanced efficacy compared to single agents across diverse AML samples, while sparing stromal cells.
  • Sensitivity to single-agent DORA and VEN correlated with distinct, nonoverlapping leukemic cell differentiation states.
  • The combination mitigated resistance observed with single agents in monocytic AML subtypes (M4/M5, CD14+).
  • Increased expression of MAPK14 and BCL2 was noted in monocytic and undifferentiated leukemias, respectively.
  • Dual targeting diminished the association between transcriptomic signatures (monocyte-like, progenitor-like) and drug sensitivities.

Conclusions:

  • The combination of doramapimod (DORA) and venetoclax (VEN) offers a promising strategy for enhanced efficacy in AML.
  • Exploiting complementary drug sensitivity profiles based on leukemic differentiation state is key to overcoming AML heterogeneity.
  • Dual targeting of p38 MAPK and BCL2 presents an opportunity for broad therapeutic benefit in challenging AML landscape.

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