Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA.
Biological Sciences Collegiate Division, The University of Chicago, Chicago, IL, USA.
Mol Diagn Ther. 2017 Dec;21(6):621-631. doi: 10.1007/s40291-017-0292-x.
The advent of targeted therapeutics has greatly improved outcomes of chronic myeloid leukemia (CML) patients. Despite increased efficacy and better clinical responses over cytotoxic chemotherapies, many patients receiving targeted drugs exhibit a poor initial response, develop drug resistance, or undergo relapse after initial success. This inter-individual variation in response has heightened the interest in studying pharmacogenetics and pharmacogenomics (PGx) of cancer drugs. In this review, we discuss the influence of various germline and somatic factors on targeted drug response in CML. Specifically, we examine the role of genetic variants in drug metabolism genes, i.e. CYP3A family genes, and drug transporters, i.e. ABC and SLC family genes. Additionally, we focus on acquired somatic variations in BCR-ABL1, and the potential role played by additional downstream signaling pathways, in conferring resistance to targeted drugs in CML. This review highlights the importance of PGx of targeted therapeutics and its potential application to improving treatment decisions and patient outcomes.
靶向治疗的出现极大地改善了慢性髓性白血病（CML）患者的预后。尽管与细胞毒性化疗相比，靶向药物具有更高的疗效和更好的临床反应，但许多接受靶向药物治疗的患者初始反应不佳、产生耐药性或在初始成功后复发。这种个体间反应的差异增加了对癌症药物的药物遗传学和药物基因组学（PGx）的研究兴趣。在这篇综述中，我们讨论了各种种系和体细胞因素对 CML 中靶向药物反应的影响。具体来说，我们研究了药物代谢基因（即 CYP3A 家族基因）和药物转运体（即 ABC 和 SLC 家族基因）中遗传变异的作用。此外，我们还关注 BCR-ABL1 获得性体细胞变异，以及下游信号通路的潜在作用，这些作用导致 CML 中靶向药物耐药。本综述强调了靶向治疗药物遗传学的重要性及其在改善治疗决策和患者结局方面的潜在应用。
