Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.
Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.
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抗原和有效载荷靶标的平行基因组改变介导多克隆获得对三阴性乳腺癌的sacituzumab govitecan的临床抗性。
DOI：
10.1158/2159-8290.cd-21-0702
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发表时间：
2021-10
期刊：
影响因子：
28.2
通讯作者：
Ellisen LW
中科院分区：
文献类型：
--
作者：
Coates JT;Sun S;Leshchiner I;Thimmiah N;Martin EE;McLoughlin D;Danysh BP;Slowik K;Jacobs RA;Rhrissorrakrai K;Utro F;Levovitz C;Denault E;Walmsley CS;Kambadakone A;Stone JR;Isakoff SJ;Parida L;Juric D;Getz G;Bardia A;Ellisen LW
对抗体-药物缀合物sacituzumab govitecan的获得性耐药性可以通过影响抗原（TROP 2）或有效载荷靶标（TOP 1）的基因组改变而产生。Sacituzumab govitecan（SG）是第一个被批准用于三阴性乳腺癌的抗体-药物缀合物（ADC），其结合了与拓扑异构酶-1（TOP 1）抑制剂有效载荷缀合的抗TR 0 P2抗体hRS 7。我们试图通过治疗前和进展后标本的RNA和全外显子组测序来确定SG耐药的机制。一名表现出新发进展的患者缺乏TROP 2表达，这与在对SG有深度、延长反应的患者中观察到的TROP 2表达和TACSTD 2/TROP 2的局灶性基因组扩增相反。在这种情况下，获得性基因组耐药分析显示一个系统发育分支包含典型的TOP 1 E418 K耐药突变和随后的移码TOP 1突变，而一个独特的分支表现出新的TACSTD 2/TROP 2 T256 R错义突变。重构实验表明，TR 0 P2 T256 R通过有缺陷的质膜定位和减少的hRS 7细胞表面结合赋予SG抗性。这些发现突出了与对SG的抗性相关的抗体和有效载荷靶标中的平行基因组改变。这些发现强调了TROP 2作为反应决定因素，并揭示了个体患者不同转移性亚克隆中涉及直接抗体和药物有效载荷靶点的获得性SG耐药机制。这项研究强调了SG的特异性，并说明了这些机制将如何为克服ADC耐药的治疗策略提供信息。 这篇文章在本期专题中突出显示，
Acquired resistance to the antibody–drug conjugate sacituzumab govitecan can arise through genomic alterations affecting either the antigen (TROP2) or the payload target (TOP1). Sacituzumab govitecan (SG), the first antibody–drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance. This article is highlighted in the In This Issue feature,
影响因子：
14.9
作者：
Fiorani P;Chillemi G;Losasso C;Castelli S;Desideri A
通讯作者：
Desideri A