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Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers

Mohd Mughees1,2, Moises J Tacam1,2, Alex W Tan1,2

  • 1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Molecular Cancer Therapeutics
|May 13, 2025
PubMed

Insights

Myeloid cell leukemia-1 (MCL-1) drives resistance to MEK inhibitors (MEKis) in aggressive breast cancer. Combining MCL-1 inhibitors with MEKis overcomes this resistance, restoring sensitivity and warranting further investigation for triple-negative breast cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The MAPK pathway is implicated in aggressive breast cancer progression and resistance to targeted therapies like MEK inhibitors (MEKis).
  • Acquired resistance to MEKis, such as AZD6244 (selumetinib), limits their clinical efficacy in solid tumors.
  • Myeloid cell leukemia-1 (MCL-1) was identified as a key factor in MEKi resistance via synthetic-lethality screening.

Purpose of the Study:

  • To investigate the role of MCL-1 in acquired resistance to the MEK inhibitor AZD6244 in aggressive breast cancer.
  • To determine if combined inhibition of MCL-1 and MEK can overcome AZD6244 resistance.
  • To evaluate the therapeutic potential of this combination strategy in preclinical models.

Main Methods:

  • Established AZD6244-resistant cell lines (MDA-MB-231-R, SUM149-R) from triple-negative breast cancer models.
  • Characterized resistant cells for proliferation, colony formation, stemness, anchorage-independent growth, and MCL-1 expression.
  • Utilized MCL-1 knockdown and pharmacological inhibition (MCL-1i) in combination with MEKi (AZD6244) in vitro and in vivo.

Main Results:

  • Resistant cells exhibited increased proliferation, colony formation, stemness, anchorage-independent growth, and elevated MCL-1 expression.
  • MCL-1 knockdown in resistant cells reduced proliferation, colony formation, and increased apoptosis via pro-apoptotic proteins (PUMA, NOXA, BAK, BAX).
  • Combination therapy of MCL-1i and MEKi effectively overcame AZD6244 resistance in vitro and restored sensitivity in vivo.

Conclusions:

  • MCL-1 is a critical mediator of acquired resistance to MEK inhibitors in aggressive triple-negative breast cancer.
  • Combined inhibition of MCL-1 and MEK represents a promising strategy to overcome MEKi resistance.
  • This combination warrants further clinical investigation for treating triple-negative and inflammatory breast cancers.

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