Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia

Abstract

Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

“…Small-molecule SET inhibitors have already been identified, and they have shown promise in inhibiting oncogenic signaling and malignant cell behavior [21,32,[44][45][46]. In accordance with the major theme of this review, a recent study demonstrated that combination of SET targeting and tyrosine kinase inhibitor provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia [34]. Apart of small-molecules targeting the PIPs, the novel series of orally bioavailable and nontoxic PP2A reactivator molecules with profound in vivo therapeutic activities in KRAS mutant lung cancers and castration-resistant prostate cancer [47,48], provide a very encouraging example that PP2A indeed is druggable [14,39].…”

Matrine induced G0/G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia (T-ALL) cells

“…T-ALL constitutes 10-15% of childhood ALLs and 25% of adult ALLs. An effective chemotherapy combination for T-ALL has not been developed yet, and firstline therapy fails in 25% of pediatric and more than 50% of adult cases [1,2]. Recent studies have demonstrated that new treatments targeting specific genes or molecular pathways in cancer patients are more efficient and less toxic.…”

“…Recent studies have demonstrated that new treatments targeting specific genes or molecular pathways in cancer patients are more efficient and less toxic. Thus, targeted treatment and the determination of related oncogenes have a priority in terms of patient survival and occurrence of toxicity [2]. Therefore, new treatment options should be developed for these cases by determining new molecular targets.…”

“…T-ALL is characterized by different gene and chromosome aberrations, including chromosomal translocations in the T-cell receptor (TCR) genes, abnormal expression of oncogenes, deletions, somatic gene mutations, as well as by alterations of signaling pathways and dysregulation of microR-NAs (miRNAs) [2]. miRNAs are small noncoding RNAs about 22 nucleotides long which downregulate gene expression at the post-transcriptional level; they can inhibit translation or induce mRNA degradation by binding to the 3'-UTR region of the targeted mRNA.…”

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

“…In AML, SET is highly dependent on MYC-transcriptional activity and recruitment of RUNX1 and GATA2 on its promoter [102]. By impairing SET binding to PP2A, with molecules like FTY720 [82,105], CM-1231 [106], or OP449 [107,108] it is possible to re-establish PP2A activity, inhibiting tumor growth [91,109] and overcoming therapeutic resistance in preclinical models [92,108]. SET is known to interact with SETBP1 (SET-binding protein 1), which protects SET from protease cleavage.…”