Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor among the most lethal cancers. ARID1A has a dual role in oncogenic and tumor-suppressive functions, depending on the type of cancer. However, its role in SCLC remains unclear. Herein, we showed that ARID1A was highly expressed and correlated with prognosis in SCLC. In vitro and in vivo investigations manifested that ARID1A inhibited cell survival, proliferation, and tumor growth, functioning as a gatekeeper for cell proliferation and a caretaker of genome stability in SCLC cells. Mechanistically, ARID1A transcriptionally represses c-MYC and PARP1 expression. ARID1A depletion triggered replication stress response (RSR), DNA double-strand breaks (DSBs), and PI3K/AKT pathway activation, which could be counteracted by c-MYC or PARP1 silencing. These findings establish ARID1A as a critical antagonist of c-MYC and PARP1 signaling, coordinating proliferation control and genomic integrity maintenance. Furthermore, we revealed that ARID1A loss confers therapeutic vulnerability to the BET inhibitor (JQ1). The ARID1A-targeting compound BRD-K98645985 exhibited potent single-agent antitumor activity and synergized with JQ1 to suppress SCLC progression, highlighting a novel combinatorial therapeutic strategy. Collectively, our findings elucidate ARID1A as a critical regulator of SCLC pathogenesis through its dual control of proliferation and genomic stability while revealing novel therapeutic vulnerabilities that can be exploited through ARID1A-targeting strategies and BET inhibitor combinations.
[1]Chinese Univ Hong Kong, Affiliated Hosp 2, Sch Med, Shenzhen & Longgang Dist Peoples Hosp Shenzhen, Shenzhen 518172, Peoples R China.
[2]Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China.
[3]Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China.
[4]Kunming Med Univ, Acad Biomed Engn, Yunnan Key Lab Breast Canc Precis Med, Kunming 650500, Yunnan, Peoples R China.
[5]Kunming Med Univ, Peking Univ Canc Hosp, Yunnan Key Lab Breast Canc Precis Med, Yunnan Canc Hosp,Yunnan Hosp,Affiliated Hosp 3, Kunming 650118, Yunnan, Peoples R China.
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