Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL

Yaqi Zhao, Nicholas J Short, Hagop M Kantarjian, Ti-Cheng Chang, Pankaj S Ghate, Chunxu Qu, Walid Macaron, Nitin Jain, Beenu Thakral, Aaron H Phillips, Joseph Khoury, Guillermo Garcia-Manero, Wenchao Zhang, Yiping Fan, Hui Yang, Rebecca S Garris, Lewis F Nasr, Richard W Kriwacki, Kathryn G Roberts, Marina Konopleva, Elias J Jabbour, Charles G Mullighan
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Abstract

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance.
B 细胞 ALL 对伊妥珠单抗奥佐加米星的反应和耐药性的基因组决定因素
伊诺珠单抗-奥佐加米星(InO)是一种抗体-药物共轭物,能将卡利昔明传递给表达 CD22 的细胞。在一组接受过 InO 治疗的 B 细胞急性淋巴细胞白血病患者的回顾性队列中,我们试图了解对 InO 反应的基因组决定因素。在11%(3/27)的InO治疗后复发肿瘤样本中观察到获得性CD22突变。每个样本都有多个CD22突变,CD22逃逸的机制包括蛋白截短、蛋白失稳和表位改变。容易出错的DNA损伤修复(替代性末端连接、错配修复缺陷)导致的高突变推动了CD22的逃逸。观察到TP53、ATM和CDKN2A的获得性功能缺失突变,表明G1/S DNA损伤检查点的损害是逃避InO诱导的细胞凋亡的一种机制。总之,调节 CD22 表达和 DNA 损伤反应的基因改变会影响 InO 的疗效。本研究阐明的抗原丢失内外的CD22靶向治疗逃逸策略为改进治疗方法和克服耐药性提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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