LINC01235 promotes genomic copy number amplification in breast cancer cells.

Despite the development of HER2-targeting drugs such as trastuzumab and T-DXd,treatment resistance remains a substantial challenge, often leading to relapse and distantmetastasis. Tumor heterogeneity in HER2-positive breast cancer drives the evolution ofresistant clones following therapeutic stress. However, the targetable drivers of anti-HER2treatment resistance have not been sufficiently unraveled. Therefore, this study aimed touse neoadjuvant targeted therapy cohorts and a patient-derived organoid in vitro treatmentmodel to uncover the potential targetable drivers of anti-HER2 treatment resistance. Wefound that LINC01235 significantly enhanced DNA replication licensing and chromosomalinstability, fostering clonal expansion and evolution, and ultimately increasing resistance totherapeutic interventions. LINC01235 regulates global H3K27ac, H3K9ac, and H3K36me3modifications; promotes H2A.Z expression in regulatory regions; and increases theaccessibility of DNA licensing factors to their promoter regions. We also identified XRCC5as a key component for maintaining genomic stability, which is vital for LINC01235's rolein replication licensing. Furthermore, we explored therapeutic strategies targetingLINC01235, including the use of antisense oligonucleotides or ATR inhibitors, whichshowed promise in overcoming treatment resistance. These findings underscore thepivotal role of LINC01235 in driving resistance mechanisms and highlight novel avenuesfor targeted therapies to improve the outcomes of patients with HER2-positive breast cancer.