Patient-derived Organoid Platform for Evaluating Drug Sensitivity and Identifying Long Noncoding RNA LINC01235 as A New RNA Therapeutics to Overcome Chemoresistance in Breast Cancer

Background and Objectives: Triple-negative breast cancer (TNBC) remains one of the most challenging types of cancer to treat, primarily due to chemoresistance. Here, we aim at identifying a long non-coding RNA (lncRNA) as a novel therapeutic target to overcome this chemoresistance, employing a patient-derived organoid (PDO) platform. Using bioinformatics analysis, we uncovered LINC01235, a lncRNA promoting cancer stemness and epithelial-mesenchymal transition, as a TNBC-specific driver that mediates chemoresistance. LINC01235 overexpression predicts poor patient survival. In our preliminary studies, LINC01235 depletion inhibited TNBC spheroid and xenograft growth. Notably, silencing LINC01235 sensitized TNBC cells to different chemotherapeutic drugs. Hypothesis: We hypothesize that we can effectively utilize the PDO as a cancer precision medicine platform to uncover LINC01235 as a new RNA therapeutics to overcome chemoresistance. Study Design: We will delineate the clinicalpathological and prognostic significance of LINC01235 using patients’ samples. The PDO platform will be used to determine if LINC01235 RNAi therapeutics synergizes with different chemotherapy agents. scRNAseq will be performed to identify chemoresistance mechanisms and response signature in LINC01235-overexpressing TNBC. Outcomes: This study will not only discover a novel function of LINC01235 in TNBC tumorigenesis and its potential as a therapeutic target, but also develop an effective PDO platform for drug screening and evaluation of novel therapeutics, which will be a valuable tool for the cancer research community and ultimately lead to better treatment options for cancer patients.