Codelivery of Ponatinib and SAR302503 by Active Bone-Targeted Polymeric Micelles for the Treatment of Therapy-Resistant Chronic Myeloid Leukemia

Abstract

Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapy-resistant CML.

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

“…Inhibition of Bcr-Abl was reported to result in downregulation of STAT3 via JAK and MEK pathways [36], and ponatinib has been reported to inhibit phosphorylation of JAK2 both in BaF3/T315I cells in vitro and in leukemia models in vivo [37]. Therefore, we analyzed if the JAK2/STAT3 pathway was affected by ponatinib (Figure 4E).…”

CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia

“…Over the past ten years, increasing attention has been directed toward investigating multi-pronged targeted therapeutic strategies to manage the clinical problem of primary or evolving IM resistance. [26][27][28] At present, more and more evidence indicates that combined treatment plays a vital role in handling IM resistance. HDACs can regulate oncogene and tumor suppressor gene activities, which thereby play a vital part in tumorigenesis.…”

The impact of molecular tumor profiling on the design strategies for targeting myeloid leukemia and EGFR/CD44-positive solid tumors

“…A targeted NDDS for the co-delivery of ponatinib and SAR302503 (selective JAK2 inhibitor) for efficient CML treatment was developed by Mu and co-workers [ 47 ]. The authors employed alendronate-decorated PLA–PEG micelles for BM targeting.…”