KRAS-Driven Hypertranscription and Metastatic Dissemination in Colorectal Cancer Could be Overcome by Targeting the
Dengbo Ji1, Haizhao Yi2, Ming Li1
1Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Rd., Haidian District, Beijing, China, 100142.
Abstract:
Colorectal cancer (CRC) becomes highly lethal upon progression to advanced or metastatic stages. Treatment options are particularly limited for refractory metastatic CRC (mCRC) harboring KRAS mutations. In this study, we established a series of patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) from mCRC patients to identify effective therapeutic compounds. We employed RNA sequencing to characterize the transcriptomic profiles of KRAS-mutant microsatellite stable (MSS) PDOs and analyzed single-cell RNA sequencing data to examine features of KRAS-mutant CRC epithelial cells. Transcriptomic analysis revealed that KRAS mutations induce elevated global transcription activity in both PDOs and epithelial cells. A large-scale drug screen of 786 Food and Drug Administration (FDA)-approved anticancer agents identified the acridine compound amsacrine hydrochloride as a potent inhibitor of PDOs and cell lines. We subsequently synthesized a series of acridine derivatives for further screening. Finally, LS-1-2 was discovered to overcome chemotherapy resistance and suppress liver metastasis in KRAS-mutated CRC. Mechanistically, LS-1-2 binds to non-muscle myosin heavy chain IIA (NMHC IIA), blocking its phosphorylation. This inhibition disrupts the PI3K/ERK/FOXO/PLK1 signaling pathway and attenuates KRAS-driven hypertranscription. In conclusion, the acridine derivative LS-1-2 emerges as a promising candidate from this preclinical investigation, providing a rationale for future clinical trials in KRAS-mutant CRC.
Insights
Researchers identified LS-1-2, a novel acridine derivative, effective against KRAS-mutated colorectal cancer (CRC). This compound overcomes chemotherapy resistance and reduces liver metastasis by targeting NMHC IIA and disrupting key signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Metastatic colorectal cancer (mCRC) with KRAS mutations presents limited treatment options.
- Patient-derived models are crucial for identifying effective therapies for refractory mCRC.
Purpose of the Study:
- To identify novel therapeutic compounds for KRAS-mutant colorectal cancer.
- To investigate the mechanism of action of potential drug candidates.
Main Methods:
- Established patient-derived organoids (PDOs) and xenografts (PDXs) from mCRC patients.
- Utilized RNA sequencing and single-cell RNA sequencing for transcriptomic profiling.
- Conducted a large-scale drug screen of FDA-approved anticancer agents and synthesized acridine derivatives.
Main Results:
- KRAS mutations were found to elevate global transcription activity in CRC.
- Amsacrine hydrochloride showed initial inhibitory effects; LS-1-2 demonstrated superior efficacy.
- LS-1-2 overcame chemotherapy resistance and suppressed liver metastasis in preclinical models.
- LS-1-2 inhibits NMHC IIA phosphorylation, disrupting PI3K/ERK/FOXO/PLK1 signaling and KRAS-driven hypertranscription.
Conclusions:
- The acridine derivative LS-1-2 is a promising therapeutic candidate for KRAS-mutant colorectal cancer.
- LS-1-2's mechanism involves targeting NMHC IIA and associated signaling pathways.
- Further clinical trials are warranted to evaluate LS-1-2 in patients with KRAS-mutated CRC.
