Jack J, Small G W, Brown C C, Havener T M, McLeod H L, Motsinger-Reif A A, Richards K L
Department of Statistics, North Carolina State University, Raleigh, NC, USA.
Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
Pharmacogenomics J. 2018 May 22;18(3):467-473. doi: 10.1038/tpj.2017.41. Epub 2017 Dec 5.
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.
阐明治疗性单克隆抗体（MAb）的耐药机制具有挑战性，因为它们很难在非人类模型中进行研究。因此，我们开发了一种策略，用于在体外对药物敏感性进行基因定位，以识别那些改变对利妥昔单抗反应性的基因。利妥昔单抗是一种治疗性抗CD20单克隆抗体，对B细胞恶性肿瘤患者有显著疗效。我们通过全基因组定位分析发现了新的基因座，并对其中一个基因CBLB进行了功能验证，该基因在淋巴瘤细胞中被敲低时会导致对利妥昔单抗产生耐药性。这项研究证明了全基因组定位在发现具有潜在临床优势的新生物学机制方面的实用性。
