Oaxaca Derrick M, Yang-Reid Sun Ah, Ross Jeremy A, Rodriguez Georgialina, Staniswalis Joan G, Kirken Robert A
Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
Department of Mathematical Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
Tumour Biol. 2016 Sep;37(9):12643-12654. doi: 10.1007/s13277-016-5179-7. Epub 2016 Jul 21.
Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.
酪氨酸激酶抑制剂（TKIs）显著提高了慢性髓性白血病（CML）患者的预期寿命；然而，由于与TKIs相关的继发性脱靶机制，患者最终会对TKI治疗产生耐药性或出现不良反应。表现出TKI耐药性的CML患者发生侵袭性和对药物不敏感疾病的风险更高。耐药性CML通常是由于靶向癌蛋白的药物结合位点内的自发突变而产生的。为了更好地理解TKI耐药性CML患者的耐药机制，将BCR-ABL转化的细胞系KCL22与浓度不断增加的伊马替尼一起培养6周。随后，分离出携带T315I守门基因突变的亲代KCL22细胞系的耐药衍生物，并通过多药筛选研究其对TKI的药物敏感性。在这种临床相关的伊马替尼耐药性CML细胞系中，发现波纳替尼和福司可林的协同组合可降低细胞活力，这在其他CML细胞系中也被证明是有效的。总之，本研究为BCR-ABL驱动的CML的生物学基础提供了新的见解，并为研究T315I CML患者的新治疗策略提供了潜在的理论依据。
