Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death.

Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response. We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and -resistant preclinical models. Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC. Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.

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