Profitós-Pelejà Núria, Santos Juliana Carvalho, Marín-Niebla Ana, Roué Gaël, Ribeiro Marcelo Lima
Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.
Department of Hematology, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
Cancers (Basel). 2022 Feb 9;14(4):860. doi: 10.3390/cancers14040860.
The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte's life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.
源自B细胞受体（BCR）的增殖和存活信号是成熟淋巴细胞生命的关键方面。BCR信号失调被认为是不同亚型B细胞非霍奇金淋巴瘤（B-NHL）肿瘤存活的重要因素。在过去十年中，BCR相关激酶作为合理的治疗靶点的出现，导致了几种靶向布鲁顿酪氨酸激酶（BTK）、脾酪氨酸激酶（SYK）或磷脂酰肌醇3激酶（PI3K）的小分子抑制剂的开发和批准，为标准化学免疫疗法提供了替代治疗选择，并使其中一些药物成为抗淋巴瘤药物库中的宝贵资产。尽管它们最初有效，但这些精准医学策略受到侵袭性B细胞淋巴瘤如弥漫性大B细胞淋巴瘤（DLBCL）和套细胞淋巴瘤（MCL）原发性耐药的限制，尤其是第一代BTK抑制剂的情况。在这些患者中，靶向BCR的药物往往无法产生持久反应，几乎所有病例最终都会因继发性耐药而进展，预后不佳。本综述将讨论我们目前对抗抗原依赖性和抗原非依赖性BCR信号在DLBCL和MCL中的作用的理解，并将涵盖已批准的抑制剂和正在早期临床前研究中评估的研究性分子。我们将讨论这些分子的作用机制及其脱靶/靶向效应如何影响其有效性并导致毒性，以及我们目前的知识如何支持开发更特异性的抑制剂和新的、基于合理依据的联合疗法，用于管理MCL和DLBCL患者。
