Bibliographic Details
| Title: |
Targeting SOS1 overcomes imatinib resistance with BCR-ABL independence through uptake transporter SLC22A4 in CML |
| Authors: |
Yanjun Liu, Chuting Li, Rui Su, Zhao Yin, Guiping Huang, Juhua Yang, Zhendong Li, Keda Zhang, Jia Fei |
| Source: |
Molecular Therapy: Oncolytics, Vol 23, Iss , Pp 560-570 (2021) |
| Publisher Information: |
Elsevier, 2021. |
| Publication Year: |
2021 |
| Collection: |
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: |
SOS1, imatinib sensitivity, resistance with BCR-ABL independence, CML, SLC22A4, RNA-seq, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: |
Resistance to the BCR-ABL inhibitor imatinib mesylate poses a major problem for the treatment of chronic myeloid leukemia. Imatinib resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, sometimes there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent imatinib mesylate resistance remains to be elucidated. SOS1, a guanine nucleotide exchange factor for Ras protein, affects drug sensitivity and resistance to imatinib. The depletion of SOS1 markedly inhibits cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulates the expression of SLC22A4, a member of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that intracellular accumulation of imatinib is accompanied by upregulation of SLC22A4 through SOS1 inhibition in both sensitive and resistant chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in chronic myeloid leukemia cells with resistance and BCR-ABL independence. Altogether these findings indicate that targeting SOS1 inhibition promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2372-7705 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2372770521001595; https://doaj.org/toc/2372-7705 |
| DOI: |
10.1016/j.omto.2021.11.010 |
| Access URL: |
https://doaj.org/article/bdf5d9c72c494d8ba975006ae84f5c9c |
| Accession Number: |
edsdoj.bdf5d9c72c494d8ba975006ae84f5c9c |
| Database: |
Directory of Open Access Journals |
