Jung Won Chun , Hye Won Shon , Jeong Eun Gong , Mi Rim Lee , Yu-Sun Lee , Sung Joon Kim , Sumin Kang , Sunshin Kim , Kyung Yong Lee , Sang Myung Woo , In Rae Cho , Woo Hyun Paik , Woo Jin Lee , Sun-Young Kong , Ji Kon Ryu , Yong-Tae Kim , Sang Hyub Lee , Yun-Hee Kim
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引用次数: 0
Abstract
Background
Oxaliplatin is a commonly used platinum-based chemotherapy drug for patients with pancreatic cancer (PC). Drug resistance is a major challenge in PC treatment, underscoring the urgent need for new approaches. Targeting DNA damage repair, one of the factors responsible for platinum resistance, is an attractive strategy to overcome drug resistance. This study aimed to investigate the potential of the ATR inhibitor BAY 1895344 in improving the drug responsiveness of oxaliplatin-resistant PC.
Methods
Oxaliplatin-resistant PC cells (CFPAC-1 and Capan-2) were selected and treated with oxaliplatin, BAY 1895344, or a combination of both in vivo and in vitro. Their combinatorial effects on the DNA damage response (DDR) signaling pathway, apoptosis, and extent of DNA damage were evaluated using appropriate methods. Patient response was predicted using organoid models.
Results
Combination treatment with BAY 1895344 and oxaliplatin exhibited a synergistic effect on both PC cell lines, with the effect being more pronounced on Capan-2. Additionally, the combination treatment substantially suppressed phospho-Chk1, a coordinator of DDR and cell cycle checkpoints. Mechanistically, ATR inhibition augmented the DNA damage induced by oxaliplatin, leading to mitotic catastrophe and cell death. Furthermore, in an in vivo study using a tumor-bearing xenograft mouse model, the combination treatment markedly reduced tumor growth. This synergistic effect was confirmed in patient-derived organoids with poor response to oxaliplatin.
Conclusion
ATR inhibition enhanced the anticancer effect of oxaliplatin, suggesting that this combination treatment could be an effective therapeutic strategy for overcoming platinum resistance in PC.
期刊介绍:
BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.