Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India.
School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
Indian J Med Res. 2024 May;159(5):455-467. doi: 10.25259/ijmr_1716_22.
Oncogenes play a crucial part in human cancer development, and when particular drugs obstruct the proteins produced by these oncogenes, the tumoural process can be ceased. For instance, in chronic myeloid leukaemia (CML), all pathological traits are associated with a single oncogene, BCR-ABL1. CML is a triphasic cancerous disorder of haematopoietic stem cells, marked by a balanced translocation between chromosomes 9 and 22, leading to the genesis of a Philadelphia chromosome encompassing the BCR-ABL1 fusion gene. This fusion oncogene further produces a constitutive active tyrosine kinase protein, enhancing the downstream signalling pathways and constitutes cancer. The treatment for CML has been entirely altered from chemotherapy and immunotherapy to targeted therapy with the emergence of tyrosine kinase inhibitors (TKIs) which inhibit BCR-ABL1 kinase activity. However, the inhibitory mechanism of TKIs is constrained by BCR-ABL1 dependent and independent resistance mechanisms, prompting the exploration of novel therapeutics through extensive clinical trials to develop next-generation drugs with enhanced potency. The persistent challenges posed by CML have motivated researchers to seek innovative strategies for its eradication, such as the application of the genome editing tool CRISPR/Cas9. This review provides insights into existing CML diagnoses, treatment modalities, resistance mechanisms, drugs under trial phases and new potential therapeutic drugs. Furthermore, the review looks ahead to a visionary perspective wherein the CRISPR/Cas9 approach holds the potential to evolve into a prospective curative measure for CML.
癌基因在人类癌症发展中起着至关重要的作用,当特定的药物阻断这些癌基因产生的蛋白质时,肿瘤过程就可以停止。例如,在慢性髓系白血病(CML)中,所有病理特征都与单个癌基因 BCR-ABL1 有关。CML 是一种造血干细胞的三相癌性疾病,其特征是染色体 9 和 22 之间的平衡易位,导致包含 BCR-ABL1 融合基因的费城染色体的产生。这个融合癌基因进一步产生一个组成性激活的酪氨酸激酶蛋白,增强下游信号通路,构成癌症。随着酪氨酸激酶抑制剂(TKI)的出现,CML 的治疗已经完全从化疗和免疫疗法转变为靶向治疗,这些抑制剂抑制 BCR-ABL1 激酶活性。然而,TKI 的抑制机制受到 BCR-ABL1 依赖性和非依赖性耐药机制的限制,促使通过广泛的临床试验探索新的治疗方法,开发具有增强效力的下一代药物。CML 持续存在的挑战促使研究人员寻求创新的策略来消除它,例如应用基因组编辑工具 CRISPR/Cas9。本综述深入探讨了现有的 CML 诊断、治疗方式、耐药机制、临床试验中的药物以及新的潜在治疗药物。此外,该综述还展望了一个富有远见的视角,即 CRISPR/Cas9 方法有可能演变成 CML 的一种有前途的治疗方法。