Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia

Abstract

Notwithstanding intensified therapy, a considerable fraction of T-cell acute lymphoblastic leukemia (T-ALL) patients face a dismal prognosis due to primary resistance to treatment and relapse, raising the need for more efficient and targeted therapies. Hedgehog (HH) signaling is a major developmental pathway frequently deregulated in cancer, for which a role in T-ALL is emerging. Mounting evidence suggests that ligand-independent activation of HH pathway occurs in cancer including T-ALL, emphasizing the necessity of dissecting the complex interplay between HH and other signaling pathways regulating activation. In this work, we present a therapeutically relevant crosstalk between HH signaling and the glucocorticoid receptor (NR3C1) pathway acting at the level of GLI1 transcription factor. GLI inhibitor GANT61 and dexamethasone were shown to exert a synergistic anti-leukemic effect in vitro in T-ALL cell lines and patient-derived xenografts. Mechanistically, dexamethasone-activated NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase and HDAC1 deacetylase. Increased GLI1 acetylation was associated with compromised transcriptional activity and reduced protein stability. In summary, our study identifies a novel crosstalk between GLI1 and NR3C1 signaling pathway which could be exploited in HH-dependent malignancies to increase therapeutic efficacy.

Genetically Engineered Human Pituitary Corticotroph Tumor Organoids Exhibit Divergent Responses To Glucocorticoid Receptor Modulators

“…Non-canonical Hh signaling pathways have been classified as 1) Type I pathways involving signaling through PTCH1 independent of SMO, 2) Type II pathways involving signaling through SMO independent of GLI, and 3) SMO-independent activation of GLI such as that observed in the current study [42, 43]. In support of our findings, crosstalk between GLI and GR (NR3C1) signaling has been reported in T cell acute lymphoblastic leukemia [44]. In addition, studies in the adult stomach demonstrated that the Hh pathway is critical for the regulation of somatostatin and SSTR signaling [45, 46].…”

Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia

“…82 Most of the approved drugs work on the smoothened receptor, but recent studies have also identified the GLI1 TF as an important target of choice in T-ALL. 82 Bongiovanni et al 83 proposed targeting the crosstalk between Hedgehog signaling and the GR pathway as an effective therapeutic strategy in T-ALL. This derives from a synergistic antileukemic effect observed in T-ALL cell lines and in PDX models upon combinatorial treatment with the GLI inhibitor GANT61 and dexamethasone.…”

“…In the proposed mechanism, dexamethasone-induced NR3C1 expression can favor the recruitment of PCAF acetyltransferase and the dissociation of HDAC1 deacetylase, leading to GLI1 acetylation and impairment of GLI1 transcriptional activity and protein stability. 83…”

Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5′AMP-Activated Kinase Inactivation

“…Although recent studies have shown that HH signaling is active in a subgroup of T-ALL cases and may play a role in T-ALL progression, only modest therapeutic activity has been found using HH inhibitors (iHHs) in monotherapy [21,22]. Thus, identification of signaling pathways that alter sensitivity to iHHs under metabolic conditions encountered within the tumor microenvironment is imperative for increasing their therapeutic efficacy [23]. In the present report, we analyzed how nutrient starvation (mimicked through serum deprivation) altered iHHs sensitivity in T-ALL cells.…”