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ARID1A Governs Genomic Stability and Proliferation in SCLC via c-MYC/PARP1 Suppression Driving Vulnerability to BET

Guozhen Cao1,2,3, Liying Ma1,2,3, Xueqin Dai4

  • 1The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen 518172, P. R. China.

Research (Washington, D.C.)
|October 6, 2025
PubMed

Insights

ARID1A acts as a tumor suppressor in small cell lung cancer (SCLC), inhibiting proliferation and maintaining genome stability. Its loss creates vulnerabilities exploitable by BET inhibitors and ARID1A-targeting drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis.
  • The role of ARID1A, known for its dual function in cancer, remains unclear in SCLC.

Purpose of the Study:

  • To investigate the role of ARID1A in SCLC pathogenesis.
  • To explore ARID1A's impact on cell proliferation, genome stability, and therapeutic vulnerabilities in SCLC.

Main Methods:

  • In vitro and in vivo experiments were conducted.
  • ARID1A expression, c-MYC and PARP1 repression, replication stress response (RSR), DNA double-strand breaks (DSBs), and PI3K/AKT pathway activation were analyzed.
  • Therapeutic efficacy of ARID1A-targeting compounds and BET inhibitors (JQ1) was evaluated.

Main Results:

  • ARID1A is highly expressed in SCLC and correlates with better prognosis.
  • ARID1A inhibits SCLC cell survival, proliferation, and tumor growth by repressing c-MYC and PARP1.
  • ARID1A depletion induces RSR, DSBs, and PI3K/AKT activation, which are counteracted by c-MYC or PARP1 silencing.
  • ARID1A loss sensitizes SCLC to BET inhibitors.
  • An ARID1A-targeting compound (BRD-K98645985) showed antitumor activity and synergized with JQ1.

Conclusions:

  • ARID1A functions as a tumor suppressor in SCLC, controlling proliferation and genomic stability.
  • ARID1A antagonizes c-MYC and PARP1 signaling, maintaining cellular homeostasis.
  • Targeting ARID1A and combining with BET inhibitors presents a promising therapeutic strategy for SCLC.

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