| Accession |
PRJCA044370 |
| Title |
Paneth-like transition drives resistance to KRAS/EGFR Dual Therapy in Colorectal Cancer |
| Relevance |
Medical |
| Data types |
Single cell sequencing
|
| Organisms |
Mus musculus
Homo sapiens
|
| Description |
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. |
| Sample scope |
Monoisolate |
| Release date |
2025-09-12 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
| 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
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
|
2022YFC2305400
|
|
|
|
| Submitter |
Yijun
Gao (gaoyj@sysucc.org.cn)
|
| Organization |
Sun Yat-sen University Cancer Center |
| Submission date |
2025-08-06 |
