DNA replication stress and mitotic catastrophe mediate sotorasib addiction in KRASG12C-mutant cancer

Journal of Biomedical Science

Research

Ching-Yao Yang¹  Chien-Hui Chan²  Yu-Ling Jhuang²  Li-Wen Chiou²  Yung-Ming Jeng³ 

[1] Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, 100, Taipei, Taiwan;Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan;Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan;Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan;Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, 100, Taipei, Taiwan;

关键词: Sotorasib;    Drug addiction;    KRAS;    Replication stress;    Mitotic catastrophe;   

DOI  :  10.1186/s12929-023-00940-4

 received in 2022-12-12, accepted in 2023-06-18,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration for treating KRASG12C-mutant non-small-cell lung cancer (NSCLC). Clinical trials on the therapeutic use of sotorasib for cancer have reported promising results. However, KRASG12C-mutant cancers can acquire resistance to sotorasib after treatment. We incidentally discovered that sotorasib-resistant (SR) cancer cells are addicted to this inhibitor. In this study, we investigated the mechanisms underlying sotorasib addiction.MethodsSotorasib-resistant cells were established using KRASG12C-mutant pancreatic cancer and NSCLC cell lines. Cell viability in the presence or absence of sotorasib and in combination with multiple inhibitors was assessed through proliferation assay and annexin V/propidium iodide (PI) flow cytometry assays. The mechanisms underlying drug addiction were elucidated through 5-bromo-2′-deoxyuridine (BrdU) incorporation assay, immunofluorescence staining, time-lapse microscopy, and comet assay. Furthermore, a subcutaneous xenograft model was used to demonstrate sotorasib addiction in vivo.ResultsIn the absence of sotorasib, the sotorasib-resistant cells underwent p21Waf1/Cip1-mediated cell cycle arrest and caspase-dependent apoptosis. Sotorasib withdrawal resulted in robust activation of mitogen-activated protein kinase (MAPK) pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo.ConclusionsWe elucidated the mechanisms underlying the sotorasib addiction of cancer cells. Sotorasib addiction appears to be mediated through MAPK pathway hyperactivity, DNA damage, replication stress, and mitotic catastrophe. Moreover, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer.

【 授权许可】

CC BY   
© The Author(s) 2023

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