Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Bathinda, 151001, India.
School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India.
Med Oncol. 2021 Jan 16;38(1):10. doi: 10.1007/s12032-021-01462-5.
Chronic myeloid leukemia (CML), a myeloproliferative hematopoietic cancer, is caused by a genetic translocation between chromosomes 9 and 22. This translocation produces a small Philadelphia chromosome, which contains the Bcr-Abl oncogene. The Bcr-Abl oncogene encodes the BCR-ABL protein, upregulates various signaling pathways (JAK-STAT, MAPK/ERK, and PI3K/Akt/mTOR), and out of which the specifically highly active pathway is the PI3K/Akt/mTOR pathway. Among early treatments for CML, tyrosine kinase inhibitors (TKIs) were found to be the most effective, but drug resistance against kinase inhibitors led to the discovery of novel alternative therapies. At this point, the PI3K/Akt/mTOR pathway components became new targets due to stimulation of this pathway in TKIs-resistant CML patients. The current review article deals with reviewing the scientific literature on the PI3K/Akt/mTOR pathway inhibitors listed in the National Cancer Institute (NCI) drug dictionary and proved effective against multiple cancers. And out of those enlisted inhibitors, the US FDA has also approved some PI3K inhibitors (Idelalisib, Copanlisib, and Duvelisib) and mTOR inhibitors (Everolimus, Sirolimus, and Temsirolimus) for cancer therapy. So far, several inhibitors have been tested, and further investigations are still ongoing. Even in Imatinib, Nilotinib, and Ponatinib-resistant CML cells, a dual PI3K/mTOR inhibitor, BEZ235, showed antiproliferative activity. Therefore, by considering the literature data of these reviews and further examining some of the reported inhibitors, which proved effective against the PI3K/Akt/mTOR signaling pathway in multiple cancers, may improve the therapeutic approaches towards TKI-resistant CML cells where the respective signaling pathway gets upregulated.
慢性髓性白血病（CML）是一种骨髓增生性造血系统癌症，由染色体 9 和 22 之间的基因易位引起。这种易位产生了一个小的费城染色体，其中包含 Bcr-Abl 癌基因。Bcr-Abl 癌基因编码 BCR-ABL 蛋白，上调各种信号通路（JAK-STAT、MAPK/ERK 和 PI3K/Akt/mTOR），其中特别高活性的通路是 PI3K/Akt/mTOR 通路。在 CML 的早期治疗中，发现酪氨酸激酶抑制剂（TKI）最为有效，但激酶抑制剂的耐药性导致了新的替代治疗方法的发现。此时，由于 TKI 耐药性 CML 患者中该通路的刺激，PI3K/Akt/mTOR 通路的成分成为新的靶点。本文综述了 NCI 药物词典中列出的针对 PI3K/Akt/mTOR 通路抑制剂的科学文献，这些抑制剂已被证明对多种癌症有效。在这些被列入的抑制剂中，美国 FDA 还批准了一些 PI3K 抑制剂（idelalisib、copanlisib 和 duvelisib）和 mTOR 抑制剂（everolimus、sirolimus 和 temsirolimus）用于癌症治疗。到目前为止，已经测试了几种抑制剂，并且仍在进行进一步的研究。即使在伊马替尼、尼洛替尼和泊那替尼耐药的 CML 细胞中，双重 PI3K/mTOR 抑制剂 BEZ235 也显示出抗增殖活性。因此，考虑到这些综述的文献数据，并进一步检查一些已被证明对多种癌症的 PI3K/Akt/mTOR 信号通路有效的报道抑制剂，可能会改善针对 TKI 耐药的 CML 细胞的治疗方法，其中相应的信号通路会被上调。
