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MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia

Laura Mazzera1,2, Manuela Abeltino2, Guerino Lombardi1

  • 1Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna "Bruno Ubertini", Brescia, Italy.

Leukemia
|June 29, 2023
PubMed

Insights

A newly discovered MEK1/2/BCR::ABL1 signaling loop drives resistance to tyrosine kinase inhibitors (TKIs) in leukemia. Blocking MEK1/2 with arsenic trioxide (ATO) re-sensitizes leukemia cells to treatment.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • Tyrosine kinase inhibitor (TKI) resistance is a major hurdle in treating Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).
  • Understanding novel resistance mechanisms is crucial for developing effective therapeutic strategies against TKI-resistant leukemia.

Purpose of the Study:

  • To elucidate the mechanistic basis of TKI resistance in chronic myeloid leukemia.
  • To investigate the potential of arsenic trioxide (ATO) and MEK1/2 inhibitors in overcoming TKI resistance.

Main Methods:

  • Investigated a novel MEK1/2/BCR::ABL1 signaling loop in TKI-resistant leukemia cells.
  • Utilized pharmacological blockade of MEK1/2 and arsenic trioxide (ATO) treatment.
  • Assessed the effects of combined MEK1/2 inhibition and ATO in cellular and murine models of BCR::ABL1-induced leukemia.

Main Results:

  • Activated MEK1/2 forms a complex with BCR::ABL1, BCR, and ABL1, promoting phosphorylation events that lead to drug resistance.
  • MEK1/2 inhibition disrupts this complex, causing dephosphorylation, restoring tumor suppressor functions, and sensitizing cells to ATO.
  • Combination therapy with MEK1/2 inhibitor Mirdametinib and ATO significantly improved survival in a mouse model of TKI-resistant leukemia.

Conclusions:

  • A MEK1/2/BCR::ABL1 signaling loop is identified as a key driver of TKI resistance in chronic myeloid leukemia.
  • Targeting MEK1/2 in combination with ATO demonstrates significant anti-leukemic activity and overcomes TKI resistance.
  • This combination therapy holds therapeutic promise for treating TKI-resistant Philadelphia chromosome-positive leukemia.

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