Wang Wei, Sun Yue, Liu Xiaobo, Kumar Shaji K, Jin Fengyan, Dai Yun
Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China.
Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, United States.
Front Oncol. 2022 Apr 27;12:859455. doi: 10.3389/fonc.2022.859455. eCollection 2022.
The introduction of various targeted agents into the armamentarium of cancer treatment has revolutionized the standard care of patients with cancer. However, like conventional chemotherapy, drug resistance, either preexisting (primary or intrinsic resistance) or developed following treatment (secondary or acquired resistance), remains the Achilles heel of all targeted agents with no exception, either genetic or non-genetic mechanisms. In the latter, emerging evidence supports the notion that intracellular signaling pathways for tumor cell survival act as a mutually interdependent network extensive cross-talks and feedback loops. Thus, dysregulations of multiple signaling pathways usually join forces to drive oncogenesis, tumor progression, invasion, metastasis, and drug resistance, thereby providing a basis for so-called "bypass" mechanisms underlying non-genetic resistance in response to targeted agents. In this context, simultaneous interruption of two or more related targets or pathways (an approach called dual-targeted therapy, DTT), either linear or parallel inhibition, is required to deal with such a form of drug resistance to targeted agents that specifically inhibit a single oncoprotein or oncogenic pathway. Together, while most types of tumor cells are often addicted to two or more targets or pathways or can switch their dependency between them, DTT targeting either intrinsically activated or drug-induced compensatory targets/pathways would efficiently overcome drug resistance caused by non-genetic events, with a great opportunity that those resistant cells might be particularly more vulnerable. In this review article, we discuss, with our experience, diverse mechanisms for non-genetic resistance to targeted agents and the rationales to circumvent them in the treatment of cancer, emphasizing hematologic malignancies.
各种靶向药物引入癌症治疗手段后，彻底改变了癌症患者的标准治疗方式。然而，与传统化疗一样，耐药性，无论是预先存在的（原发性或固有耐药性）还是治疗后产生的（继发性或获得性耐药性），仍然是所有靶向药物的致命弱点，无一例外，无论是遗传机制还是非遗传机制。在非遗传机制方面，新出现的证据支持这样一种观点，即肿瘤细胞存活的细胞内信号通路构成一个相互依存的网络，存在广泛的相互作用和反馈回路。因此，多种信号通路的失调通常共同作用，驱动肿瘤发生、进展、侵袭、转移和耐药，从而为靶向药物非遗传耐药背后的所谓“旁路”机制提供了基础。在这种情况下，需要同时阻断两个或更多相关靶点或通路（一种称为双靶点治疗，DTT的方法），无论是线性抑制还是平行抑制，以应对这种对特异性抑制单一癌蛋白或致癌通路的靶向药物的耐药形式。总体而言，虽然大多数类型的肿瘤细胞通常依赖于两个或更多靶点或通路，或者可以在它们之间切换依赖性，但靶向固有激活或药物诱导的补偿性靶点/通路的双靶点治疗将有效地克服非遗传事件引起的耐药性，而且那些耐药细胞可能特别更容易受到攻击。在这篇综述文章中，我们结合自身经验，讨论了靶向药物非遗传耐药的多种机制以及在癌症治疗中规避这些机制的基本原理，重点是血液系统恶性肿瘤。
