Department of Internal Medicine, University of South Florida.
Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
Curr Opin Hematol. 2018 Mar;25(2):154-161. doi: 10.1097/MOH.0000000000000403.
Chronic myeloid leukemia (CML) is hallmarked by the presence of fusion protein kinase derived from a reciprocal translocation between chromosome 9 and 22, breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) 1, causing aberrant regulation of the downstream pathways leading to unchecked CML leukemia stem cells (LSCs) proliferation. Since the discovery of tyrosine kinase inhibitors (TKI), CML, once a fatal disease, has become a chronic illness if managed appropriately. Changing treatment landscape has unsurfaced the challenge of TKI resistance that is clinically difficult to overcome.
In this review, we discuss the concept of TKI resistance and pathways leading to the resistance which allows for a survival advantage to CML LSCs. Aside from BCR-ABL-dependent mechanisms of resistance which involves aberrant expression in the regulatory pumps involving efflux and influx of the TKI affecting drug bioavailability, activation of alternate survival pathways may be accountable for primary or secondary resistance. Activation of these pathways, intrinsically and extrinsically to LSCs, may be mediated through various upstream and downstream signaling as well as conditions affecting the microenvironment. Several therapeutic approaches that combine TKI with an additional agent that inhibits the activation of an alternate pathway have been studied as part of clinical trials which we will discuss here.
We categorize the resistance into BCR-ABL-dependent and BCR-ABL-independent subgroups to further describe the complex molecular pathways which can potentially serve as a therapeutic target. We further discuss novel combination strategies currently in early or advanced phase clinical trials aimed to overcome the TKI resistance. We further highlight the need for further research despite the tremendous strides already made in the management of CML.
慢性髓细胞白血病（CML）的特征是存在源自染色体 9 和 22 之间的相互易位的融合蛋白激酶，断裂点簇区（BCR）-Abelson 白血病病毒（ABL）1，导致下游途径的异常调节，导致不受控制的 CML 白血病干细胞（LSCs）增殖。自发现酪氨酸激酶抑制剂（TKI）以来，如果得到适当的管理，CML 曾经是一种致命疾病，现在已成为一种慢性疾病。治疗领域的变化凸显了 TKI 耐药性的挑战，临床上难以克服。
在这篇综述中，我们讨论了 TKI 耐药性的概念以及导致耐药性的途径，这为 CML LSCs 的生存优势提供了可能。除了涉及涉及 TKI 外流和内流的调节泵的异常表达从而影响药物生物利用度的 BCR-ABL 依赖性耐药机制外，替代存活途径的激活也可能是导致原发性或继发性耐药的原因。这些途径在 LSCs 内外的激活可能通过各种上游和下游信号以及影响微环境的条件来介导。我们将在这里讨论的几个联合 TKI 与抑制替代途径激活的额外药物的治疗方法已作为临床试验的一部分进行了研究。
我们将耐药性分为 BCR-ABL 依赖性和 BCR-ABL 非依赖性亚组，以进一步描述潜在的治疗靶点的复杂分子途径。我们进一步讨论了目前处于早期或晚期临床试验阶段的新型联合策略，旨在克服 TKI 耐药性。我们进一步强调了尽管在 CML 管理方面已经取得了巨大进展，但仍需要进一步研究。
