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Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

Changjie Wu1, Junfang Lyu1, Eun Ju Yang1

  • 1Faculty of Health Sciences, University of Macau, Avenida da Universidade, 999078, Taipa, Macau SAR, China.

Nature Communications
|August 12, 2018
PubMed

Insights

ARID1A deficiency creates a vulnerability in colorectal cancer cells, making them sensitive to aurora kinase A (AURKA) inhibition. Targeting AURKA offers a new therapeutic strategy for ARID1A-mutated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • ARID1A, a tumor suppressor in the SWI/SNF complex, is frequently mutated in various cancers.
  • ARID1A deficiency presents potential therapeutic targets in oncology.
  • Understanding ARID1A's role is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the synthetic lethal interaction between ARID1A and aurora kinase A (AURKA) in colorectal cancer (CRC).
  • To elucidate the mechanism underlying the synthetic lethality between ARID1A and AURKA.
  • To evaluate the therapeutic potential of targeting AURKA in ARID1A-deficient CRC.

Main Methods:

  • Utilized pharmacological and genetic approaches to perturb AURKA activity in CRC cells.
  • Assessed the impact of AURKA inhibition on the proliferation of ARID1A-deficient CRC cells.
  • Investigated the transcriptional regulation of AURKA by ARID1A and its downstream effects on cell cycle regulators.

Main Results:

  • ARID1A-deficient CRC cells exhibit synthetic lethality with AURKA.
  • ARID1A loss leads to enhanced AURKA transcription and persistent CDC25C activation.
  • Inhibition of AURKA in ARID1A-deficient cells causes G2/M arrest, multinucleation, and apoptosis.

Conclusions:

  • A novel synthetic lethality between ARID1A and AURKA was identified in colorectal cancer.
  • ARID1A negatively regulates AURKA transcription; its loss upregulates AURKA.
  • Targeting the AURKA-CDC25C pathway is a promising therapeutic strategy for ARID1A-mutated CRC.

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