Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, 151401, Bathinda, India.
Med Oncol. 2023 Sep 15;40(10):300. doi: 10.1007/s12032-023-02161-z.
Chronic myeloid leukemia (CML) is characterized by presence of Philadelphia chromosome, which harbors BCR-ABL oncogene responsible for encoding BCR-ABL oncoprotein. This oncoprotein interferes with cellular signaling pathways, resulting in tumor progression. Among these pathways, PI3K/Akt/mTOR pathway is significantly upregulated in CML. Tyrosine kinase inhibitors (TKIs) are current standard therapy for CML, and they have shown remarkable efficacy. However, emergence of TKIs drug resistance has necessitated investigation of novel therapeutic approaches. Components of PI3K/Akt/mTOR pathway have emerged as attractive targets in this context, as this pathway is known to be activated in TKIs-resistant CML cells/patients. Inhibiting this pathway may provide a complementary approach to improving TKIs' efficacy and treatment outcomes. Given previous research indicating that miRNAs play an inhibitory role in cancer, current study used computational tools to identify miRNAs that specifically target pathway's core components. A comprehensive analysis was performed, resulting in identification of 111 miRNAs that potentially target PI3K/Akt/mTOR pathway. From this extensive list, 7 miRNAs was selected for further investigation based on their consistent downregulation across leukemia subtypes. Except for hsa-miR-199a-3p, remaining six miRNAs have been extensively studied in acute myeloid leukemia (AML). Given high similarity between AML and CML, it is believed that six miRNAs which are not studied in context of CML may also be advantageous for curing chemoresistance in CML. Building upon this knowledge, it is reasonable to speculate that a combination therapy approach involving use of miRNAs alongside TKIs may offer improved therapy for TKIs-resistant CML compared to TKIs monotherapy alone.
慢性髓性白血病 (CML) 的特征是存在费城染色体，该染色体携带有 BCR-ABL 癌基因，负责编码 BCR-ABL 癌蛋白。这种癌蛋白干扰细胞信号通路，导致肿瘤进展。在这些通路中，PI3K/Akt/mTOR 通路在 CML 中显著上调。酪氨酸激酶抑制剂 (TKI) 是目前治疗 CML 的标准疗法，已显示出显著疗效。然而，TKI 耐药的出现使得需要探索新的治疗方法。在这种情况下，PI3K/Akt/mTOR 通路的成分已成为有吸引力的靶点，因为已知该通路在 TKI 耐药的 CML 细胞/患者中被激活。抑制该通路可能为提高 TKI 的疗效和治疗结果提供一种补充方法。鉴于先前的研究表明 miRNA 在癌症中发挥抑制作用，本研究使用计算工具来鉴定专门针对该通路核心成分的 miRNA。进行了全面的分析，确定了 111 个可能靶向 PI3K/Akt/mTOR 通路的 miRNA。在这个广泛的列表中，根据它们在白血病亚型中一致下调的情况，选择了 7 个 miRNA 进行进一步研究。除了 hsa-miR-199a-3p 外，其余 6 个 miRNA 在急性髓系白血病 (AML) 中得到了广泛研究。鉴于 AML 和 CML 之间的高度相似性，据信在 CML 背景下未研究的 6 个 miRNA 可能也有助于治疗 CML 的化疗耐药性。在此基础上，有理由推测，与 TKI 单药治疗相比，联合使用 miRNA 和 TKI 的组合治疗方法可能为 TKI 耐药的 CML 提供更好的治疗效果。
