Long noncoding RNA, RAMS11, promotes DNA damage response in colorectal cancer

Colorectal cancer remains a leading cause of cancer-related mortality worldwide, with approximately 30% of patients developing resistance to standard chemotherapy. Tumors that exhibit defects in DNA damage response (DDR) and DNA repair pathways exhibit increased genomic instability, which can manifest as resistance, underscoring the clinical significance of therapeutic targeting of DDR. While protein-coding drivers in colorectal cancer have been extensively characterized, persistent therapeutic challenges emphasize the necessity of elucidating novel mechanisms driving cancer development. Here, we found that the long noncoding RNA (lncRNA) RAMS11 is significantly upregulated in metastatic colorectal cancer, particularly in tumors harboring p53 mutations, as revealed by analyses of The Cancer Genome Atlas (TCGA) datasets. p53-mutant metastatic CRC, a population normally reliant on the ATR/Chk1 checkpoint for survival. However, from small-molecule drug screening, we discovered that high RAMS11 cells showed resistance to ATR and CHK1 inhibitors. While RAMS11 drives a state of high replication stress, as evidenced by increased RAD51 foci in RAMS11-overexpressing cells, it simultaneously confers profound resistance to ATR and CHK1 inhibitors. Mechanistically, we resolve this paradox by demonstrating that RAMS11 attenuates the checkpoint response, leading to a blunted pChk1 activation even under replication stress. We find these cells are now critically dependent on an alternative repair pathway, Homologous Recombination (HR), to resolve the DNA damage. Indeed, our functional studies confirm that knockdown of RAMS11 significantly impairs HR repair capacity. This work identifies that RAMS11 reroutes DDR dependencies in cells, revealing a new mechanism of intrinsic chemoresistance and suggesting a synthetic lethal strategy targeting the HR pathway. Collectively, these findings suggest that aberrant overexpression of RAMS11 disrupts the DDR and promotes DNA replication stress, thereby leading to chemoresistance. Elucidating the mechanism of RAMS11 will provide critical insights into chemoresistance in colorectal cancer.