| 项目编号 |
PRJCA044370 |
| 项目标题 |
Paneth-like transition drives resistance to KRAS/EGFR Dual Therapy in Colorectal Cancer |
| 涉及领域 |
Medical |
| 数据类型 |
Single cell sequencing
|
| 物种名称 |
Mus musculus
Homo sapiens
|
| 描述信息 |
While dual KRAS and EGFR inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient derived organoids and xenografts, as well as clinical specimens, we discovered that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state - a secretory lineage typically confined to the intestinal crypt. Lineage tracing revealed that CRC cells evade KRAS/EGFR-targeted therapy by transitioning into Paneth-like state. Through integrated transcriptomic analysis and CRISPR/Cas9 genetic screening, we identified SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevented the Paneth-like transition, restored drug sensitivity, and synergized with KRAS/EGFR inhibitors across multiple preclinical models. These findings reveal that SMAD1/FGFR3 axis triggers Paneth-like Plasticity to drive KRAS/EGFR therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance. |
| 样品范围 |
Monoisolate |
| 发布日期 |
2025-09-12 |
| 出版信息 |
| PubMed ID |
文章标题 |
杂志名称 |
Doi |
发表年份 |
| 41237766
|
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
|
Cancer Cell
|
10.1016/j.ccell.2025.10.010
|
2025
|
|
|
| 项目资金来源 |
| 机构 |
项目类型 |
授权项目ID |
授权项目名称 |
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
|
2022YFC2305400
|
|
|
|
| 提交者 |
Yijun
Gao (gaoyj@sysucc.org.cn)
|
| 提交单位 |
Sun Yat-sen University Cancer Center |
| 提交日期 |
2025-08-06 |
