Drug perturbation RNA sequencing of 2 prostate cancer cell lines

Prioritizing cancer treatments at the individual patient level remains challenging, and performing co-clinical studies using patient-derived models in real-time is often not unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework to predict and validate drug sensitivity sensitivity in both a human tumors and in its their pre-existing high est-fidelity (cognate) (cognate) model(s)—for contextual in vivo validation—) by leveraging perturbational profiles of clinically-relevant oncology drugs. As proof-of-concept, we applied OncoLoop to prostate cancer (PCa) using a series of genetically engineered mouse models (GEMMs) that capture the broad spectrum of disease states, including metastatic, castration-resistant, metastatic, and neuroendocrine prostate cancer. Interrogation of published cohorts revealed that most patients were represented by at least one cognate GEMM-derived tumor (GEMM-DT), based on upon Master Regulator (MR) conservation analysis. Drugs recurrently predicted to recurrently invert MR protein activity in patients and their cognate GEMM-DTs were successfully validated, including in two cognate allografts and one cognate patient derived xenograft (PDX). OncoLoop is highly generalizable and can be extended to other cancers and potentially other pathologdiseasesies. 1728 RNAseq profiles of perturbed cell-lines with FDA-approved drugs and late-stage experimental compounds. Cell-lines were treated at a 48-hour IC20 for each drug and RNA was collected at 24 hours to minimize cell-death. Samples were prepared and sequences in batches of 96 that included 6 vehicle (DMSO) and 6 water controls. 2 replicates were taken for each drug-cell-line pair.

在个体患者层面制定癌症治疗优先级仍颇具挑战，而实时利用患者来源模型开展共临床研究往往并非不可行。为规避上述挑战，我们推出了OncoLoop——一款精准医学框架，可借助临床相关抗肿瘤药物的扰动谱，在人类肿瘤及其预先构建的高保真同源模型中预测并验证药物敏感性，以实现情境化的体内验证。
作为概念验证，我们将OncoLoop应用于前列腺癌（prostate cancer, PCa）研究，采用了一系列可覆盖疾病广谱状态的基因工程小鼠模型（GEMMs），这些状态包括转移性、去势抵抗性、转移性以及神经内分泌前列腺癌。
对已发表队列的分析显示，基于主调控因子（Master Regulator, MR）保守性分析，绝大多数患者至少可对应一个同源基因工程小鼠源肿瘤（GEMM-DT）。
可反复预测出可逆转患者及其同源GEMM-DT中MR蛋白活性的药物均得到了成功验证，其中包括两例同源异体移植瘤与一例同源患者来源异种移植瘤（PDX）。
OncoLoop具有极强的泛化性，可推广至其他癌症乃至潜在的其他病理疾病领域。
本数据集包含1728份经FDA批准药物及晚期实验性化合物处理的细胞系的RNA测序（RNAseq）图谱。
细胞系以对应药物的48小时半数抑制浓度（IC20）进行处理，并于处理后24小时收集RNA，以最大程度减少细胞死亡。
样本以96孔板为一批次进行制备与测序，每批次包含6份赋形剂（DMSO）对照与6份纯水对照。每个药物-细胞系组合均设置2次生物学重复。