論文 - 詳細
| RRC ID | 85104 |
|---|---|
| 著者 | Kwon YJ, Kim DY, Kim UI, Kim SH, Kim YH, Kim K, Kim JS. |
| タイトル | Basroparib overcomes acquired resistance to MEK inhibitors by inhibiting Wnt-mediated cancer stemness in KRAS-mutated colorectal cancer. |
| ジャーナル | Biochem Pharmacol |
| Abstract |
Mitogen-activated protein kinase (MEK) inhibitors show promise in treating KRAS-mutated cancers, including colorectal cancer (CRC). However, acquired resistance to MEK inhibitors often results in failure of effective treatment in patients with KRAS-mutated CRC. Here, we demonstrated that basroparib overcomes MEK inhibitor resistance in KRAS-G12V- or -G12D-mutated CRC. This basroparib-mediated sensitization was dependent on the KRAS mutation status and was enhanced specifically in KRAS-G12V- or -G12D-mutated cells. Additionally, when combined with MEK inhibitors, basroparib significantly reduced tumor growth in KRAS-G12V-mutated CRC xenograft models, but not in KRAS-G13D-mutated and -wild-type models. Furthermore, basroparib sensitized KRAS-G12V-mutated CRC cells with acquired resistance to MEK inhibitors. Notably, when combined with MEK inhibitors, basroparib not only suppressed tumor regrowth but also prolonged the survival of tumor models with acquired resistance to MEK inhibitors. Mechanistically, basroparib suppressed Wnt-mediated cancer stemness, a bypass mechanism for acquired resistance to MEK inhibitors in KRAS-mutated CRC. This study provides the first preclinical evidence of the relevance of basroparib in treating CRC with acquired resistance to MEK inhibitors due to APC and KRAS mutations, possibly by reducing the Wnt-mediated cancer stemness. |
| 巻・号 | 235 |
| ページ | 116842 |
| 公開日 | 2025-5-1 |
| DOI | 10.1016/j.bcp.2025.116842 |
| PII | S0006-2952(25)00104-2 |
| PMID | 40024348 |
| MeSH | Animals Cell Line, Tumor Colorectal Neoplasms* / drug therapy Colorectal Neoplasms* / genetics Colorectal Neoplasms* / metabolism Colorectal Neoplasms* / pathology Drug Resistance, Neoplasm* / drug effects Drug Resistance, Neoplasm* / physiology Humans Indoles* / administration & dosage Indoles* / pharmacology Indoles* / therapeutic use Mice Mice, Nude Mitogen-Activated Protein Kinase Kinases* / antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases* / metabolism Mutation* Neoplastic Stem Cells* / drug effects Neoplastic Stem Cells* / metabolism Neoplastic Stem Cells* / pathology Protein Kinase Inhibitors* / administration & dosage Protein Kinase Inhibitors* / pharmacology Protein Kinase Inhibitors* / therapeutic use Proto-Oncogene Proteins p21(ras)* / genetics Proto-Oncogene Proteins p21(ras)* / metabolism Wnt Signaling Pathway* / drug effects Wnt Signaling Pathway* / physiology Xenograft Model Antitumor Assays / methods |
| IF | 4.96 |
| リソース情報 | |
| 遺伝子材料 | pTcf7wtluc (RDB02968) |