Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia

Abstract

The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long‐term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr‐Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM‐resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM‐resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF‐κB, MEK‐ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS‐1145 (IκB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM‐resistant cells and reduction in the colony‐forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF‐κB signaling attenuates the survival of IM‐resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients.

Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling

“…Moreover, ABL1/2 activity and 14-3-3 proteins are critical for the assembly of MAP4K1/MAP3K1/MEK/ERK complexes, and ABL1/2 drive coupling of MAP4K1 to MAP3K1. Our data are consistent with data obtained in other cell contexts showing that ABL1 interacts with and/or phosphorylates MAP4K1 and MAP3K1 43 , 45 , 52 – 54 , and with the identification of increased MAP3K phosphopeptides in imatinib-resistant BCR-ABL1-expressing CML cells (indicates they are likely substrates) 55 .…”

Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells

“…MAP3K8 encodes mitogen-activated protein kinase kinase kinase 8, a member of serine/threonine kinase family (Paardekooper et al, 2018), which is involved in the MAPK/JNK/p38 and NFkB signaling pathway (Chorzalska et al, 2018). Overexpression of MAP3K8, also known as tumor progression locus 2 (TPL2), is correlated with poor prognosis and metastasis in patients with colorectal cancer (Pyo et al, 2018).…”

Extracellular signal-regulated kinases associate with and phosphorylate DHPS to promote cell proliferation

“…Many inhibitors targeting this pathway have been approved or tested for cancer treatments 2,8,[14][15][16] . Despite the success of several inhibitors, their efficacies are compromised by the emerging drug resistance or dose-limiting side effects [17][18][19] . Identification of more substrates regulated by this pathway may shed light on these problems.…”

“…Although many substrates of ERK1/2 have been identified to date, the diverse roles of ERK1/2 signaling within the cell suggest that there may be more yet to be identified substrates of these key kinases 17 . In addition, despite the success of inhibitors targeting the ERK1/2 pathway, their efficacies are compromised by the emerging drug resistance 18,19 . Identification of more ERK1/2 substrates may shed light on these questions.…”