PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Abstract

Key Points• CD25 is a predictive biomarker for sensitivity to PIM inhibitors in AML cells.• PIM inhibitors may prolong overall/relapse-free survival through attenuating STAT5 activation and destabilizing MYC in CD25 1 AML cells.Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

“…As expected from cell culture experiments, mice treated with AZD1208 had activated STAT signaling; this activation was significantly inhibited in mice with combination treatment. Following treatment with AZD1208, induction of PIM1 protein levels was increased, as previously reported with other PIM inhibitors [58]. These results support dual inhibitor treatment for a specific subset of T-ALL tumors expressing PIM1.…”

Protein profiling identifies mTOR pathway modulation and cytostatic effects of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia

“…PIM inhibitors have been investigated in AML cells as single agents as well as in combination, with varying potencies and cellular consequences[5,7,10,14,17,31,33–44]. Downstream mTOR targets (4E-BP1, PRAS40, eIF4B)[23,45,46] and upstream regulators (TSC2) [47] have been identified as Pim targets, and our RPPA investigations support the reports of Pim activity on mTOR signaling.…”

“…Pim-1 kinase also regulates MET receptor tyrosine kinase levels and signaling via translation through phosphorylation of eIF4B[6]. More recently, Pim inhibition has been demonstrated to suppress STAT5 activation and reduce MYC protein half-life in higher CD25-expressing subpopulations of AML cell lines[7]. Thus, inhibition of Pim kinases may be an avenue to target AML cell survival.…”

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

“…Several retrospective studies carried out in AML patients have shown that patients with a higher percentage of CD25-positive AML blasts have poor overall survival or relapse-free survival [126,127]. The enhanced CD25 expression in AMLs seems to be induced by STAT5 and MYC hyperactivation occurring in many AMLs: both STAT5 and MYC play a key role in leukemia-initiating activity [128,129].…”