KRAS-Driven Hypertranscription and Metastatic Dissemination in Colorectal Cancer Could be Overcome by Targeting the NMHC IIA/ PLK1 Signaling Axis with a Novel Acridine Derivative

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.