The NEDD8-activating enzyme inhibitor MLN4924 induces DNA damage in Ph+ leukemia and sensitizes for ABL kinase inhibitors

Abstract

The BCR-ABL1 fusion gene is the driver oncogene in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). The introduction of tyrosine kinase inhibitors (TKIs) targeting the ABL kinase (such as imatinib) has dramatically improved survival of CML and Ph+ ALL patients. However, primary and acquired resistance to TKIs remains a clinical challenge. Ph+ leukemia patients who achieve a complete cytogenetic (CCR) or deep molecular response (MR) (≥4.5log reduction in BCR-ABL1 transcripts) represent long-term survivors. Thus, the fast and early eradication of leukemic cells predicts MR and is the prime clinical goal for these patients. We show here that the first-in-class inhibitor of the Nedd8-activating enzyme (NAE1) MLN4924 effectively induced caspase-dependent apoptosis in Ph+ leukemia cells, and sensitized leukemic cells for ABL tyrosine kinase inhibitors (TKI) and hydroxyurea (HU). We demonstrate that MLN4924 induced DNA damage in Ph+ leukemia cells by provoking the activation of an intra S-phase checkpoint, which was enhanced by imatinib co-treatment. The combination of MLN4924 and imatinib furthermore triggered a dramatic shift in the expression of MCL1 and NOXA. Our data offers a clear rationale to explore the clinical activity of MLN4924 (alone and in combination with ABL TKI) in Ph+ leukemia patients

RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia

“…Neddylation is a type of important post-translational modifications (PTM) that mainly modulates protein stability. Accumulating evidences have shown that targeting the neddylation process could be an appealing strategy for anticancer therapy with particular efficacy in hematologic malignancies (Bahjat et al, 2019; Gu et al, 2014; Guo et al, 2019; Leclerc et al, 2016; Liu et al, 2018; Milhollen et al, 2010; Paiva et al, 2015; Soucy et al, 2009; Swords et al, 2018; Yin et al, 2019). On the other hand, neddylation is a specific PTM that modifies multiple Lys residues in BCR-ABL, shielding this oncoprotein to compete ubiquitination-mediated degradation, which provides a reasonable explanation on the poor in vivo efficacy of PROTAC-based degraders for BCR-ABL.…”

“…On the other hand, neddylation is a specific PTM that modifies multiple Lys residues in BCR-ABL, shielding this oncoprotein to compete ubiquitination-mediated degradation, which provides a reasonable explanation on the poor in vivo efficacy of PROTAC-based degraders for BCR-ABL. MLN4924, a NEDD8-activating E1 enzyme inhibitor, has been shown to inhibit the survival of both wild-type (WT) and T315I-BCR-ABL leukemia cells as well as leukemia-initiating cells ( Liu et al, 2018; Bahjat et al, 2019; Guo et al, 2019). Moreover, clinical trials of MLN4924 in combination with anticancer agents in acute myeloid leukemia (AML) have progressed to phase II (NCT03745352 and PEVENAZA [NCT04266795]) and III (PANTHER[NCT03268954] and PEVOLAM[NCT04090736]).…”

“…Meanwhile, accumulating evidence has shown that targeting the neddylation process could be an appealing strategy for anticancer therapy (Bhalla and Fiskus., 2016;McGrail et al, 2020;Norton et al, 2021;Xie et al, 2021). MLN4924, a NEDD8-activating E1 enzyme inhibitor, has been shown to inhibit the survival of both wild-type (WT) and T315I-BCR-ABL leukemia cells as well as leukemia-initiating cells ( Liu et al, 2018;Bahjat et al, 2019;Guo et al, 2019). Moreover, clinical trials of MLN4924 in combination with anticancer agents in acute myeloid leukemia (AML) have progressed to phase II (NCT03745352 and PEVENAZA [NCT04266795]) and III (PANTHER[NCT03268954] and PEVOLAM[NCT04090736]).…”

Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions

“…The expression levels of cleaved caspase3 and cleaved caspase7 are increased, and the expression levels of Bcl-2 and Bcl-XL are decreased in a concentration-dependent manner with the treatment of MLN4924 against different cancer cells. Apoptosis induced by pharmaceutical inhibition of NEDDylation suppresses tumor growth in leukemia [ 133 – 135 ], colorectal cancer [ 136 ], ewing sarcoma [ 137 ], urothelial carcinoma [ 138 ], head and neck squamous cell carcinoma and intrahepatic cholangiocarcinoma [ 128 , 139 ]. MLN4924-induced apoptosis includes enhancing the accumulation of CDT1 [ 140 ], inducing the dramatic accumulation of CRL E3 substrate I-kappa-B-alpha (IKB-α) [ 141 ] and increasing the expression of NOXA [ 142 ].…”

Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities

“…Since the SCF complex is also implicated in the regulation of ATF4 ubiquitination and degradation [104], limiting SCF activity via NEDD8 inhibitors may limit leukemia progression. Along these lines, NEDD8 inhibitors sensitize ALL and CML cells to ABL kinase inhibitors [105].…”