頁籤選單縮合
題名 | DNA Replication Stress and Mitotic Catastrophe Mediate Sotorasib Addiction in KRASᴳ¹²ᶜ-mutant Cancer= |
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作者 | Chiou, Li-wen; Chan, Chien-hui; Jhuang, Yu-ling; Yang, Ching-yao; Jeng, Yung-ming; |
期刊 | Journal of Biomedical Science |
出版日期 | 20230000 |
卷期 | 30 2023[民112] |
頁次 | 頁(50)1-(50)18 |
分類號 | 410.1636 |
語文 | eng |
關鍵詞 | Sotorasib; Drug addiction; KRAS; Replication stress; Mitotic catastrophe; |
英文摘要 | Background Sotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration for treating KRAS G12C‑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 investi‑ gated the mechanisms underlying sotorasib addiction. Methods Sotorasib‑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 dem‑ onstrate sotorasib addiction in vivo. Results In 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 activa‑ tion 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. Conclusions We 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 catas‑ trophe. 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. |
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