A Dual Inhibitor of Cdc7/Cdk9 Potently Suppresses T Cell Activation

Abstract

T cell activation is mediated by signaling pathways originating from the T cell receptor (TCR). Propagation of signals downstream of the TCR involves a cascade of numerous kinases, some of which have yet to be identified. Through a screening strategy that we have previously introduced, PHA-767491, an inhibitor of the kinases Cdc7 and Cdk9, was identified to impede TCR signaling. PHA-767491 suppressed several T cell activation phenomena, including the expression of activation markers, proliferation, and effector functions. We also observed a defect in TCR signaling pathways upon PHA-767491 treatment. Inhibition of Cdc7/Cdk9 impairs T cell responses, which could potentially be detrimental for the immune response to tumors, and also compromises the ability to resist infections. The Cdc7/Cdk9 inhibitor is a strong candidate as a cancer therapeutic, but its effect on the immune system poses a problem for clinical applications.

Targeting CDK9 for Anti-Cancer Therapeutics

“…Apart from the cancer entities described here, CDK9 is also involved in many other cancer entities like—pediatric Soft Tissue Sarcomas (STS) like Rhabdomyosarcoma (RMS), Ewing’s Sarcoma (ES), Synovial Sarcoma (SS) and Malignant Rhabdoid Tumors (MRT) [ 1 ]; Neuroblastoma; Primary Neuroectodermal Tumor (PNET) [ 157 ]; cervical cancer [ 158 ]; CLL [ 159 ]; Glioblastoma [ 160 ] etc. The functions of CDK9 is not just limited to cancers, but in other diseases as well like Rheumatoid arthritis [ 161 ]; cardiomyocytes development [ 162 ]; T-cell activation [ 163 ]; replication of viruses like HIV-1 and -2, EBV, CMV, HSV-1 and -2, HTLV-1 [ 95 , 164 ] etc. A great of interest and effort has therefore been invested in targeting the activation of CDK9 or promoting its degradation.…”

Targeting CDK9 for the Treatment of Glioblastoma

“…The dual CDC7/CDK9 inhibitor PHA-767491/NMS-1116354 was shown to affect signal transduction downstream of the T cell receptor (TCR) by inhibiting Erk phosphorylation, which is important for T cell activation and degrading the p105 isoform of NF-κB, which is important for regulating T cell homeostasis [ 77 ]. The inhibitory effects of CDK9 on T cell signaling and function have been speculated to contribute to the adverse immune-related symptoms that patients receiving CDK inhibitors in clinical trials may experience (see Section 4 ) [ 77 ]. Further studies focusing on the optimal timing and dosage that allows for an immunogenic response against tumor cells without detrimental effects on T cell proliferation and effector functions are warranted.…”

“…In 1994, flavopiridol became the first CDK inhibitor to enter clinical trials [ 22 ] and has now become the most frequently investigated CDK9 inhibitor in clinical trials [ 32 ]. A phase II study of flavopiridol in combination with cytarabine and mitoxantrone for patients with acute myeloid leukemia (AML) demonstrated 58% complete response [ 32 ], and in 2014, flavopiridol was granted orphan drug designation by the FDA for AML [ 77 ]. Despite this success, two other phase II trials testing flavopiridol (in primary peritoneal cancer and CLL, respectively, as listed in Table 1 ) reported only a 2% complete response to treatment [ 32 ].…”

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

“…The dual Cdc7/CDK9i PHA-767491 potently suppressed T cell activation, antigen-driven proliferation, and effector functions in vitro [101]. Specifically, the Cdc7/CDK9 blockade inhibited Erk phosphorylation in different T cell populations, suppressed TNF/IFNγ-cytokine release, and induced caspase-3dependent NF-κB p105 degradation [101]. Hence, these kinases may be involved in signal transduction downstream of the T cell receptor.…”