Precision oncology in GI-cancers: Mechanisms of action, indications and ongoing strategies to overcome primary and secondary resistance

IF 20.3 1区医学 Q1 ONCOLOGY

Seminars in cancer biology Pub Date : 2026-10-01 Epub Date: 2026-09-20 DOI:10.1016/j.semcancer.2026.102619

Laia Aceituno, Elena Valenzi, Oreste Segatto, Anna Saborowski, Arndt Vogel

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引用次数: 0

Abstract

Gastrointestinal (GI) cancers remain a leading cause of cancer mortality, with durable benefit from current therapies limited to a subset of patients. Precision oncology is expanding options by targeting recurrent, actionable alterations, most notably in cholangiocarcinoma (CCA), in genes such as FGFR2, IDH1, KRAS, BRAF and ERBB2. Here, we review the evolving therapeutic landscape, emphasizing clinical efficacy, and indications for various treatment modalities. Key therapies include FGFR inhibitors (first and next-generation; both covalent and FGFR2-selective agents), IDH1 inhibitors, KRAS and BRAF inhibitors combined with EGFR blockade and/or chemotherapy, and HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). Central mechanisms of both primary and secondary resistance are detailed, with a focus on on-target mutations and convergent off-target MAPK signaling pathways. Finally, we discuss drug-tolerant persister cells, residual tumor cell states that survive therapy without canonical genetic resistance alterations and may contribute to relapse and secondary resistance.

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gi肿瘤的精确肿瘤学：作用机制，适应症和克服原发性和继发性耐药的持续策略。

胃肠道（GI）癌症仍然是癌症死亡的主要原因，目前的治疗方法仅对一小部分患者有持久的益处。精准肿瘤学正在通过靶向复发性、可操作的改变来扩大选择范围，尤其是在胆管癌（CCA）中，如FGFR2、IDH1、KRAS、BRAF和ERBB2基因。在这里，我们回顾了不断发展的治疗前景，强调临床疗效和各种治疗方式的适应症。关键疗法包括FGFR抑制剂（第一代和下一代；共价和fgfr2选择性药物），IDH1抑制剂，KRAS和BRAF抑制剂联合EGFR阻断和/或化疗，以及her2靶向单克隆抗体，酪氨酸激酶抑制剂（TKIs）和抗体-药物偶联物（adc）。本文详细介绍了原发性和继发性耐药的主要机制，重点是靶突变和趋同脱靶MAPK信号通路。最后，我们讨论了耐药持续性细胞，残留的肿瘤细胞状态，在治疗后没有典型的遗传抗性改变，可能导致复发和继发性耐药。

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

Seminars in cancer biology 医学-肿瘤学

CiteScore

26.80

自引率

4.10%

发文量

347

审稿时长

15.1 weeks

期刊介绍： Seminars in Cancer Biology (YSCBI) is a specialized review journal that focuses on the field of molecular oncology. Its primary objective is to keep scientists up-to-date with the latest developments in this field. The journal adopts a thematic approach, dedicating each issue to an important topic of interest to cancer biologists. These topics cover a range of research areas, including the underlying genetic and molecular causes of cellular transformation and cancer, as well as the molecular basis of potential therapies. To ensure the highest quality and expertise, every issue is supervised by a guest editor or editors who are internationally recognized experts in the respective field. Each issue features approximately eight to twelve authoritative invited reviews that cover various aspects of the chosen subject area. The ultimate goal of each issue of YSCBI is to offer a cohesive, easily comprehensible, and engaging overview of the selected topic. The journal strives to provide scientists with a coordinated and lively examination of the latest developments in the field of molecular oncology.