Targeting SOS1 overcomes imatinib-Resistance with BCR-ABL-Independence through uptake transporter, SLC22A4 in CML

Abstract 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, there is no mutation in BCR-ABL sometimes, 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/resistance to imatinib. The depletion of SOS1 markedly inhibits the cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, the LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulate the expression of SLC22A4, one of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that the intracellular accumulation of imatinib is accompanied by upregulation SLC22A4 through SOS1 inhibition in both sensitive and resistant with chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in the chronic myeloid leukemia cells of resistance with BCR-ABL-Independence. Take together that targeting inhibit SOS1 promotes the imatinib sensitive and overcomes resistance with BCR-ABL-Independence by SLC22A4-mediated uptake transport.