SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

Abstract

<jats:sec><jats:title>Objective</jats:title><jats:p>Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.</jats:p></jats:sec>

The SUMO pathway in pancreatic cancer: insights and inhibition

“…34 Both ML-792 and ML-93 inhibit the growth of PDAC cells and show a significant correlation in their half-maximal growth inhibitory concentrations in a large panel of murine PDAC cell lines. 22 In sensitive pancreatic cancer models, ML-93 was effective in the double-digit nanomolar range, which was lower than the range observed using ML-792, resulting in the accumulation of cells in the G2/M phase of the cell cycle and in polyploidy with associated apoptosis. 22 These results demonstrate the importance of SUMOylation for proper mitotic progression.…”

“…22 In sensitive pancreatic cancer models, ML-93 was effective in the double-digit nanomolar range, which was lower than the range observed using ML-792, resulting in the accumulation of cells in the G2/M phase of the cell cycle and in polyploidy with associated apoptosis. 22 These results demonstrate the importance of SUMOylation for proper mitotic progression. 35 An ML-792/ML-93-derived SAE inhibitor, TAK-981, entered clinical development in 2019, with Phase 1 trials recruiting patients with any advanced or metastatic solid tumour and lymphoma (NCT03648372 and NCT04074330).…”

“…Tissuebased analysis and mRNA expression profiles have defined an aggressive PDAC subtype that shows evidence of hyperactivity of the core SUMO pathway and thereby links the SUMO pathway with less-differentiated PDACs-the basal-like subtype-and an unfavourable prognosis. 22 Mechanistic studies in PDAC link the SUMO pathway in particular with the response towards chemotherapies and to mechanisms of treatment resistance.…”

“…ML-792 and ML-93 form covalent adducts with SUMOs and thereby block SAE and the transfer of SUMOs to the E2 enzyme, UBC9. 22,34 ML-792 and ML-93 in the nanomolar range reduce the fraction of SUMO-bound UBC9 and, consequently total protein SUMOylation, with no crossreactivity with the NEDDylation and ubiquitinylation machineries; 22,34 furthermore, when screened against 366 ATPdependent enzymes, ML-792 demonstrated specificity for the SAE complex. 34 ML-792 induces a failure of mitotic progression and chromosome segregation, with a consequent increase in endoreduplication and polyploidy.…”

Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies

“…In addition, many components of the SUMO pathway, including E1, E2, and several PIAS E3 proteins were shown to be highly expressed in both B-cell lymphomas and pancreatic cancer overexpressing c-Myc. This results in higher overall SUMO conjugation and consequent vulnerability of these tumors to inhibition of SUMOylation (Hoellein et al, 2014;Biederstädt et al, 2020). Finally, we have recently shown that the SUMO pathway plays an important role, on one side, in the response of acute myeloid leukemias (AML) to standard chemotherapies (Bossis et al, 2014) and, on the other side, in the resistance of nonpromyelocytic AML to differentiation therapies using retinoic acid (Baik et al, 2018).…”