Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Paracelsus Medical University, Cancer Cluster Salzburg, Salzburg, Austria.
Department of Biosciences, Paris-Lodron-University Salzburg, Salzburg, Austria.
Acta Haematol. 2024;147(5):604-611. doi: 10.1159/000537791. Epub 2024 Feb 24.
Targeting the B-cell receptor pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates.
In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance. Here, we provide evidence that ibrutinib resistance can be attributed to aberrant mammalian target of rapamycin (MTOR) signaling.
Thus, our study proposes that combined use of MTOR inhibitors with ibrutinib could be a possible option to overcome therapy resistance in ibrutinib treated patients.
通过伊布替尼靶向 B 细胞受体通路，一种布鲁顿酪氨酸激酶的特异性抑制剂，在治疗慢性淋巴细胞白血病（CLL）患者方面显示出显著的临床疗效，因此成为一种无论风险因素如何都首选的一线治疗方案。然而，伊布替尼获得性耐药是一个主要的临床问题，需要开发新的治疗组合以提高疗效并对抗耐药的发展和临床复发率。
在这项研究中，我们对一名伊布替尼耐药的 CLL 患者进行了外显子组和转录组分析，以研究与伊布替尼耐药相关的基因和表达模式。在这里，我们提供的证据表明，伊布替尼耐药可归因于异常的哺乳动物雷帕霉素靶蛋白（mTOR）信号。
因此，我们的研究表明，联合使用 mTOR 抑制剂和伊布替尼可能是克服伊布替尼治疗患者治疗耐药的一种可行选择。
