Unlocking CML Resistance: The Potential of SET Antagonist OP449 in Combination with ABL TKIs

Chronic myeloid leukemia (CML) patients often achieve long-lasting remissions with ABL tyrosine kinase inhibitors (TKIs), but some develop resistance through various mechanisms, including BCR-ABL kinase-dependent mutations or BCR-ABL kinase-independent pathways, such as LYN overexpression. Studies indicate that BCR-ABL's presence in CML cells leads to an overproduction of the SET protein, which inhibits protein phosphatase 2A (PP2A), a key regulator of signaling proteins. The loss of PP2A function is linked to heightened BCR-ABL activity in CML blast crisis cells, and activating PP2A with certain treatments can reduce CML cell clonogenicity, irrespective of ABL TKI sensitivity. This suggests that PP2A's pharmacological activation could be a promising therapeutic strategy for CML, particularly for imatinib-resistant cases.

A novel cell-penetrating peptide, OP449, has been identified that binds to SET and counteracts its inhibitory effect on PP2A. In vitro studies with human and murine CML cell lines showed a significant increase in PP2A activity following OP449 treatment. OP449 demonstrated higher potency than the PP2A activator FTY720 and induced reduced proliferation and increased apoptosis in CML cells. Importantly, TKI-resistant mutant CML cells were also susceptible to OP449, and it displayed selectivity for BCR-ABL-positive cells. In combination with ABL TKIs, OP449 further reduced proliferation and increased apoptosis in CML cells.

Mechanistic studies revealed that OP449 treatment did not change SET protein levels but significantly reduced another PP2A inhibitor, CIP2a. OP449 also blocked BCR-ABL-mediated downstream signaling and induced the dephosphorylation and degradation of key proteins in CML cells. In vivo, OP449 showed no toxicity in non-leukemic mice and extended survival in a 32Dp210 xenograft model. Moreover, in a murine CML bone marrow transplantation model, OP449 improved survival and reduced leukemia burden, with combination treatment with nilotinib showing enhanced effects.

In conclusion, OP449 selectively targets CML cells by antagonizing SET and enhancing PP2A activity, thereby restoring PP2A's tumor suppressor role. This validates SET antagonism as a potential target for new CML therapeutics, especially for patients with ABL TKI resistance, and supports the potential of OP449 in combination with ABL TKIs for treatment.