Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Abstract

Background Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR‐ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)‐based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR‐ABLT315I. Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin‐proteasome system and possess multiple functions during cancer progression. Methods The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b‐AP15. We explored the effect of b‐AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b‐AP15 on BCR‐ABLWT and BCR‐ABLT315I CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML. Results In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b‐AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour‐killing activity in BCR‐ABLWT and BCR‐ABLT315I CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR‐ABL in CML cells expressing BCR‐ABLWT and BCR‐ABLT315I. Moreover, b‐AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR‐ABLWT and BCR‐ABLT315I CML cells. Conclusion Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.

MitoCur‐1 induces ferroptosis to reverse vemurafenib resistance in melanoma through inhibition of USP14

“…Inhibition of USP14 has been demonstrated to induce autophagy (Han et al., 2019; Wu et al., 2022; Xu et al., 2016), apoptosis (Liao et al., 2018; Wu et al., 2022), and ferroptosis (Tsai et al., 2020), by which reversing drug resistance in breast cancer, melanoma, and chronic myeloid leukemia, etc. (Jiang et al., 2022; Selvaraju et al., 2015; Shen et al., 2020; Wu et al., 2022; Xia et al., 2019).…”

Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

“…B-AP15, an inhibitor of USP14 and UCHL5, can cooperate with imatinib to inhibit the growth of BCR-ABL-WT and BCR-ABL-T315I CML cell lines, CML xenograft tumor, and primary CML cells. 154 Meanwhile, in another study, they found that piperlongumine, isolated from piper longum L., can target USP14 and UCHL5 to inhibit the proteasome function of CML cells with or without T315I mutation, weaken the cell viability of CML cell line, induce apoptosis, and inhibit the growth of transplanted tumor. This study provides a theoretical basis for the application of piperlongumine in patients with CML resistance.…”

Targeting deubiquitinases for cancer therapy

“…b-AP15 has demonstrated the ability to induce strong oxidative stress and cell death in various cancer cells and inhibit tumor growth in mice. [78][79][80] Preclinical studies have also shown that USP14 and UCHL5 inhibitors exhibit broad antitumor activity against both nonsolid and solid tumors (e.g., multiple myeloma and hypopharyngeal carcinoma), overcoming resistance to bortezomib. 78,81 This indicates that their mechanism of action against cancer is distinct from that of 20S proteasome inhibitors.…”

“…b‐AP15 possesses an α, β‐unsaturated carbonyl moiety, which is highly prone to undergoing a Michael addition reaction with nucleophilic cysteine thiolates of DUBs. b‐AP15 has demonstrated the ability to induce strong oxidative stress and cell death in various cancer cells and inhibit tumor growth in mice 78–80 . Preclinical studies have also shown that USP14 and UCHL5 inhibitors exhibit broad antitumor activity against both nonsolid and solid tumors (e.g., multiple myeloma and hypopharyngeal carcinoma), overcoming resistance to bortezomib 78,81 .…”