Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Abstract

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

“…Our group identified that dinaciclib suppresses activation of IFNγ-induced IDO-1 upregulation in patient-derived GBM cells (Fig. 5) [47]. While IDO-1 upregulation is a common acquired resistance mechanism with global immunosuppressive effects, our findings support the incorporation of CDKi in immunotherapeutic concepts [94].…”

“…Abemaciclib induced vacuolization in patient-derived GBM models, accompanied by a high abundance of LAMP1/2/Rab7a. These late endosomal markers are formed in the early stages of methuosis (Riess et al Cell Death Discovery [47] and Fig. 2).…”

The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

“…Notably, dinaciclib was similarly able to induce CalR translocation and upregulation of the immunologically relevant marker MHC class I to an extent comparable to THZ1/5-FU combination therapy. This makes dinaciclib particularly interesting in the context of immunotherapy, as hypothesized before [ 33 , 45 ]. Hossain et al treated murine CT26 colon cancer cells for 24 h with different dinaciclib concentrations (0.05 µM–25 µM) and identified a linear increase in CalR translocation.…”

Targeting CDK9 for the Treatment of Glioblastoma

“…In addition to its ability to synergize with anti-PD1, dinaciclib can downregulate the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in glioblastoma cells, as shown in a study by Riess et al [ 74 ]. IDO is produced in response to IFN-γ and plays an important role in tryptophan metabolism by mediating the degradation of tryptophan and accumulation of kynurenine [ 11 ].…”

“…Glioblastomas exhibit high expression of IDO1, and increased IDO1 expression serves as a negative prognostic factor for patient survival [ 11 ]. Interestingly, Riess et al also demonstrated that IDO1 expression increased in two glioblastoma cell lines following TMZ treatment and that IDO1 expression was reduced in TMZ-treated cells after additional treatment with dinaciclib [ 74 ]. This suggests the potential utility of combining CDK9 inhibitors with the standard treatment of TMZ in order to mitigate any immunosuppressive effects induced by TMZ via IDO1.…”