Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Abstract

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel‐based therapy remains the first‐line treatment for metastatic castration‐resistant prostate cancer. However, dose‐limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high‐throughput kinome‐wide loss‐of‐function screen. Further drug‐gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA‐approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel‐induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)–negative DU145 and PC3 cells, but not in the AR‐positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2‐specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.

Potential drug repurposing of ruxolitinib to inhibit the JAK/STAT pathway for the treatment of patients with epithelial ovarian cancer

“…Targeting the JAK/STAT pathway can also reverse drug resistance to chemotherapy or TKIs 84–87 . For instance, inhibition of JAK1 in prostate cancer cells enhanced sensitivity of the first‐line chemotherapeutic drug, docetaxel 87 .…”

“…82 Targeting the JAK/STAT pathway can also reverse drug resistance to chemotherapy or TKIs. [84][85][86][87] For instance, inhibition of JAK1 in prostate cancer cells enhanced sensitivity of the first-line chemotherapeutic drug, docetaxel. 87 In EGFR-mutant lung adenocarcinoma, inhibition of JAK2 causes EGFR to detach from its negative regulator SOCS5, resulting in increased reexpression of tumor cell EGFR, thus, EGFR inhibitors such as erlotinib or gefitinib regain efficacy.…”

“…[84][85][86][87] For instance, inhibition of JAK1 in prostate cancer cells enhanced sensitivity of the first-line chemotherapeutic drug, docetaxel. 87 In EGFR-mutant lung adenocarcinoma, inhibition of JAK2 causes EGFR to detach from its negative regulator SOCS5, resulting in increased reexpression of tumor cell EGFR, thus, EGFR inhibitors such as erlotinib or gefitinib regain efficacy. 86 Preclinical studies of JAK2 inhibition have also shown successful blockade of STAT3 phosphorylation and reduced nuclear translocation in non-small cell lung, pancreas, breast, gastric, head and neck, hepatocellular, renal, bladder, prostate, and OC cell lines.…”

Immune Biomarkers in Blood from Sarcoma Patients: A Pilot Study

“…Only one gene (homeobox A10 (HOXA10) (NM_018951)), which was upregulated by two-fold ( p < 0.05), belonged to two gene groups: the transcriptional factor and epigenetically regulated genes ( Table 6 ). The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING Consortium 2022) (Version 11.5) ( (accessed on 20 May 2022)) software was used to predict the protein–protein interaction (PIP) in a virtual situation to show the vital interactions as well as possible signaling pathways that these dysregulated genes affect [ 25 ] ( Figure 4 ).…”

Potential applications of JAK inhibitors, clinically approved drugs against autoimmune diseases, in cancer therapy

“…Baricitinib was also approved as a treatment for COVID-19 in 2020 by the EUA and in 2022 by the FDA ( Shawky et al, 2022 ). The efficacy of baricitinib as a cancer therapy has rarely been considered so far, although one has study reported that baricitinib did not induce apoptosis of T-ALL ( Akahane et al, 2017 ), whereas synergistic effects for its combination with docetaxel were observed in androgen-receptor-negative prostate cancer cells ( Nalairndran et al, 2021 ). Potential effects on the risk of tumorigenesis have also been evaluated; one study reported that the malignancy rate in RA patients treated with baricitinib was high but not significantly different from that of the general population or of patients treated with TNF inhibitors ( Uchida et al, 2023 ).…”