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Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.
Cancer Science 2022 September 11
Small molecule induced degradation of mutant Bcr-Abl1 provides a potential approach to overcome Bcr-Abl1 tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Our previous study reported that a synthetic steroidal glycoside SBF-1 showed remarkable anti-CML activity by inducing the degradation of native Bcr-Abl1 protein. Here, we observed the comparably growth inhibition for SBF-1 in CML cells harboring T315I mutant Bcr-Abl1 in vitro and in vivo. SBF-1 triggered its degradation through disrupting the interaction between protein-tyrosine phosphatase 1B (PTP1B) and Bcr-Abl1. Using SBF-1 as a tool, we found that Tyr46 in PTP1B catalytic domain and Tyr852 in Bcr-Abl1 PH domain are critical for their interaction. Moreover, the phosphorylation of Tyr1086 within Bcr-Abl1 SH2 domain recruited the E3 ubiquitin ligase c-Cbl to catalyze K27-linked ubiquitin chains, which serve as a recognition signal for p62-dependent autophagic degradation. PTP1B dephosphorylated Bcr-Abl1 at Tyr1086 and prevented the recruitment of c-Cbl, leading to the stability of Bcr-Abl1. This study unravels the action mechanism of PTP1B in stabilizing Bcr-Abl1 protein and indicates that the PTP1B-Bcr-Abl1 interaction might be one of druggable target for TKI-resistant CML with point mutations.
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