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Inhibition of ACAA1 Restrains Proliferation and Potentiates the Response to CDK4/6 Inhibitors in Triple-Negative

Wen-Ting Peng1,2,3, Xi Jin1,2, Xiao-En Xu1,2

  • 1Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.

Cancer Research
|May 2, 2023
PubMed

Insights

Acetyl-CoA acyltransferase 1 (ACAA1) is a new therapeutic target for triple-negative breast cancer (TNBC). Inhibiting ACAA1 with trimetazidine enhances CDK4/6 inhibitor efficacy in preclinical TNBC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and poor prognosis.
  • Identifying novel therapeutic targets is crucial for improving outcomes in TNBC patients.
  • The luminal androgen receptor (LAR) subtype of TNBC is particularly aggressive.

Purpose of the Study:

  • To identify novel therapeutic targets for triple-negative breast cancer (TNBC).
  • To investigate the role of acetyl-CoA acyltransferase 1 (ACAA1) in TNBC proliferation and response to therapy.
  • To evaluate the potential of combining ACAA1 inhibition with CDK4/6 inhibitors for TNBC treatment.

Main Methods:

  • Proteomic analysis of TNBC tissues to identify differentially expressed proteins.
  • In vitro and in vivo experiments to assess the effect of ACAA1 inhibition on TNBC cell proliferation.
  • Assessment of the interaction between ACAA1 and CDK4 using molecular assays.
  • Evaluation of trimetazidine's effect on ACAA1 protein levels and its combination efficacy with abemaciclib in preclinical TNBC models.

Main Results:

  • ACAA1 was found to be highly expressed in the LAR subtype of TNBC compared to normal tissues.
  • Inhibition of ACAA1 significantly restrained TNBC proliferation.
  • ACAA1 inhibition potentiated the anti-tumor effect of the CDK4/6 inhibitor abemaciclib.
  • Mechanistically, ACAA1 inhibition blocked RB1 phosphorylation, leading to G1-S cell-cycle arrest.
  • Trimetazidine decreased ACAA1 protein levels and enhanced abemaciclib efficacy in preclinical TNBC models.

Conclusions:

  • ACAA1 is a promising therapeutic target in TNBC, particularly in ACAA1-high tumors.
  • The combination of trimetazidine and abemaciclib demonstrates potential therapeutic benefit for ACAA1-high TNBC.
  • ACAA1 may serve as a predictive biomarker for CDK4/6 inhibitor resistance in RB1-proficient TNBC patients.

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