Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor payloads.

IF 4.5 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology Pub Date : 2026-05-04 DOI:10.1016/j.jmb.2026.169841

Yves Pommier

引用次数: 0

Abstract

Here we describe the different TOP1 poisons used a "payload" for tumor-targeted anticancer therapies in comparison with the widely used first generation TOP1 poisons: Topotecan, Irinotecan and Belotecan. We review the determinants of response to tumor-targeted TOP1 poison inhibitors (TTTis) as candidate companion diagnostic (Dx) biomarkers for precision medicine and patient selection, such as high expression of surface epitopes for ADCs (Antibody Drug Conjugates), high tumor proliferation (Ki67), Schlafen 11 (SLFN11) expression, homologous recombination deficiencies (HRD/BRCAness) and expression of drug efflux transporters such as (BCRP (MXR) encoded by ABCG2. We also summarize the mechanistic rationale for combining TTTis with small molecule inhibitors of poly(ADPribose) polymerase (PARP), ATR (Ataxia Telangiectasia and Rad3-related), CHK1 (Checkpoint Kinase 1) and ATM (Ataxia Telangiectasia Mutated).

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具有拓扑异构酶I （TOP1）抑制剂有效载荷的抗体-药物偶联物（adc）反应和合理药物组合的分子决定因素。

在这里，我们描述了不同的TOP1毒药用于肿瘤靶向抗癌治疗的“有效载荷”，并与广泛使用的第一代TOP1毒药：Topotecan，伊立替康和Belotecan进行了比较。我们回顾了肿瘤靶向TOP1毒性抑制剂（TTTis）作为精确医学和患者选择的候选伴随诊断（Dx）生物标志物的反应决定因素，如adc（抗体药物偶联物）表面表位的高表达、高肿瘤增殖（Ki67）、Schlafen 11 （SLFN11）的表达、同源重组缺陷（HRD/BRCAness）和药物外排转运蛋白（BCRP (MXR)）的表达。我们还总结了TTTis联合小分子抑制剂（PARP）、ATR（共济失调毛细血管扩张和rad3相关）、CHK1（检查点激酶1）和ATM（共济失调毛细血管扩张突变）的机制原理。

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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来源期刊

Journal of Molecular Biology 生物-生化与分子生物学

CiteScore

11.30

自引率

1.80%

发文量

412

审稿时长

28 days

期刊介绍： Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.