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Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review

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Abstract

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.

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Acknowledgements

Authors acknowledge the support received from the Central University of Punjab, Bhatinda, India, in writing this manuscript. PS and VK are grateful to the Council of Scientific and Industrial Research, New Delhi, India, for the award of the fellowship for the Ph.D. degree program.

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  1. Department of Biochemistry, School of Basic & Applied Sciences, Central University of Punjab, Bathinda, 151001, India

    Priyanka Singh, Sonu Kumar Gupta, Gudia Kumari & Malkhey Verma

  2. School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Veerandra Kumar & Malkhey Verma

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Singh, P., Kumar, V., Gupta, S.K. et al. Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review. Med Oncol 38, 10 (2021). https://doi.org/10.1007/s12032-021-01462-5

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