Hedgehog Signaling and Truncated GLI1 in Cancer

226

145

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.

Section: Crosstalk Between Egfr and Other Signaling Pathwaysmentioning

confidence: 99%

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

Uribe

Marrocco

Yarden

2021

226

145

“…At this point, the Hh/GLI signaling pathway was implicated mostly in non-cancer diseases, such as holoprosencephaly and other craniofacial developmental defects, abnormal skeletal development, aberrations in the nerve sheath, and infertility [ 25 , 26 , 27 ]. More recently, this signaling cascade has been characterized as a major contributor to a wide variety of cancers, such as basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and others [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: The History Of Hedgehogmentioning

confidence: 99%

“…The repressors of the pathway (SUFU and PTCH1) are considered tumor suppressors, as their loss of function upregulates the Hh/GLI signaling activity to drive tumorigenesis [ 31 , 35 , 116 , 244 , 245 ]. It was not until recently that SUFU mutations were noted as potential drivers of disease.…”

Section: The Hh/gli Signaling Pathway In Diseasementioning

confidence: 99%

Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

Sigafoos

Paradise

Fernández-Zapico

2021

120

The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3b, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3b) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.

“…We have shown in a previous study that NT1721, an ETP chosen from a library of ETPs because of its potent antitumor activity against various solid and non-solid tumors, attenuated hedgehog/GLI signaling through downregulation of GLI transcription factors [27]. Aberrant hedgehog/GLI signaling promotes tumorigenesis, tumor progression, metastasis and drug resistance in various types of cancers [28,29]. Here we show that treatment with NT1721 mediated GLI1 downregulation in CTCL cells, which was associated with decreased STAT3 activation and reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL).…”

Section: Introductionmentioning

confidence: 99%

Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma

Lin

Kowolik

Xie

et al. 2021

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs.