- 作者: Li-Wen Chiou, Chien-Hui Chan, Yu-Ling Jhuang, Ching-Yao Yang & Yung-Ming Jeng
- 作者服務機構: 1.Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan 2.Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan 3.Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan 4.Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
Background Sotorasib is the frst 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 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) fow cytometry assays. The mechanisms underlying
drug addiction were elucidated through 5-bromo-2′-deoxyuridine (BrdU) incorporation assay, immunofuorescence
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 efects 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 efects of
sotorasib addiction; this strategy may provide clinical beneft for patients with cancer - 中文關鍵字:
- 英文關鍵字: Sotorasib, Drug addiction, KRAS, Replication stress, Mitotic catastrophe