First Department of Internale Medicine-Hematology, University General Hospital in Prague, 128 08 Prague, Czech Republic.
Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, 128 53 Prague, Czech Republic.
Int J Mol Sci. 2020 Mar 18;21(6):2081. doi: 10.3390/ijms21062081.
Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20 century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.
非霍奇金淋巴瘤（NHL）是起源于成熟淋巴细胞在分化的各个阶段发生恶性转化的复杂过程中的淋巴肿瘤。世界卫生组织（WHO）的 NHL 分类承认有 90 多种具有独特病理生理学和预后的疾病单位。自 20 世纪末以来，我们对淋巴瘤亚型的分子生物学的认识不断加深，这导致了新型可靶向药物靶点的确定，以及随后对新型抗淋巴瘤药物的测试和临床批准，从而显著改善了患者的预后。尽管取得了巨大的进展，但由于耐药性的发展，我们控制甚至根除恶性淋巴瘤克隆的努力经常受到阻碍，从而导致需要应对复发或治疗耐药性疾病的未满足的医疗需求。更好地了解导致固有或获得性耐药性的分子机制，可能会导致设计更有效的一线治疗算法，这些算法基于可靠的预测标志物或个性化的挽救治疗，旨在通过针对对先前治疗线耐药的淋巴瘤细胞的弱点来克服耐药克隆。本综述重点介绍了我们对 NHL 治疗中临床使用的遗传毒性和靶向药物耐药的分子机制的历史和最新进展。
