Targeting the TGFβ signalling pathway in disease - PubMed (original) (raw)

Review

. 2012 Oct;11(10):790-811.

doi: 10.1038/nrd3810. Epub 2012 Sep 24.

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Review

Targeting the TGFβ signalling pathway in disease

Rosemary J Akhurst et al. Nat Rev Drug Discov. 2012 Oct.

Abstract

Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

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Figures

Figure 1

Figure 1. Schematic overview of the canonical, SMAD-dependent TGFβ signalling pathway

The transforming growth factor-β (TGFβ) ligands are synthesized as a large latent TGFβ complex consisting of mature dimeric TGFβ associated with its latency-associated peptide (LAP) and a latent TGFβ-binding protein (LTBP) (not shown). Upon activation, TGFβ dimers induce heteromeric complex formation between specific type II and type I receptors (such as TGFβ receptortype II (TpRII) andTpRI, respectively). Type II receptors then transphosphorylate the type I receptors, which propagate the signal into the cell by phosphorylating TGFβ receptor-specific SMADs (R-SMADs: SMAD2 and SMAD3). They form heteromeric complexes with the common mediator SMAD (co-SMAD: SMAD4) and translocate to the nucleus. Once in the nucleus, the R-SMAD-co-SMAD complex preferentially associates with the genomic SMAD-binding element (SBE) in a sequence-specific manner. However, high-affinity binding of the R-SMAD-co-SMAD complex with the SBE generally occurs in concert with other DNA-binding transcription factors that bind to distinct sequences adjacent to the SBE. The nuclear proteins SKI and SNO (also known as SKIL) antagonize the transcriptional regulation by SMADs. An inhibitory SMAD (I-SMAD), SMAD7, inhibits the TGFβ pathway through multiple mechanisms, including by mediating the degradation of the type I receptor, inhibiting phosphorylation of R-SMADs by the type I receptor kinase or inhibiting the formation of the R-SMAD–co-SMAD complex. In addition to regulating transcription, R-SMADs can modulate microRNA (miRNA) biogenesis by facilitating the processing of primary miRNA into precursor miRNA in the nucleus. The co-SMAD is not required for the regulation of miRNA biosynthesis by R-SMADs. ‘mG’ and ‘AAAAA’ represent 5′ capping and 3′ polyadenylation of mRNAs, respectively.

Figure 2

Figure 2. Schematic representation of non-canonical TGFβ signalling and crosstalk with other signalling pathways

In the non-canonical pathways, the activated transforming growth factor-β (TGFβ) receptor complex transmits a signal through other factors, such as TNF receptor associated factor 4 (TRAF4) or TRAF6, TGFβ-activated kinase 1 (TAK1), p38 mitogen-activated protein kinase (p38 MAPK), RHO, phosphoinositide 3-kinase (PI3K)-AKT, extracellular signal-regulated kinase (ERK), JUN N-terminal kinase (JNK) or nuclear factor-KB (NF-kB). TGFβ signalling can be influenced by pathways other than the canonical and non-canonical TGFβ signalling pathways, such as the WNT, Hedgehog, Notch, interferon (IFN), tumour necrosis factor (TNF) and RAS pathways. The crosstalk between TGFβ and other pathways defines the activities of TGFβ to propagate spatial- and temporal-specific signals. miRNA, microRNA; ROCK, RHO-associated protein kinase; R-SMAD, receptor-specific SMAD; TpR, TGFβ receptor. ‘mG’ and ‘AAAAA’ represent 5′ capping and 3′ polyadenylation of mRNAs, respectively.

Figure 3

Figure 3. Biphasic activities of the TGFβ signalling pathway during tumorigenesis: from the tumour suppressor to the tumour promoter

Transforming growth factor-β (TGFβ) has biphasic actions during tumorig enesis, suppressing tumorigenesis at early stages but promoting tumour progression later on, which is the underlying paradigm for the action of TGFβ during disease progression in general and thus complicates the development of therapies targeting TGFβ signalling. The light grey arrows indicate a positive feedforward loop resulting in higher levels of TGFβ, which is a feature of non-neoplastic as well as neoplastic diseases. The current goal in cancer therapy is to downmodulate excessive levels of TGFβ ligands and to target the tumour-progressing versus the tumour-suppressing arm of TGFβ action; the latter goal will almost certainly require more-specific second-generation drugs. CTGF, connective tissue growth factor; EMT, epithelial-mesenchymal transition; IL, interleukin; PTHRP, parathyroid hormone-related protein; TAMs, tumour-associated macrophages; TANs, tumour-associated neutrophils; VEGF, vascular endothelial growth factor.

Figure 4

Figure 4. TGFβ effects on immune cells

Transforming growth factor-p (TGFβ) has effects on most immune cell types. The figure depicts the activity of TGFβ on immune cell subsets that is relevant to human diseases. M1→M2 and N1→N2 indicate polarization of macrophages and neutrophils, respectively, from type I to type II. IgA, immunoglobulin A; TH, T helper; TReg, regulatory T.

Figure 5

Figure 5. Schematic representation of therapeutic approaches for blocking TGFβ signalling

Transforming growth factor-p (TGFβ) signalling can be inhibited by: sequestering ligands using soluble receptor ectodomain constructs (ligand traps) derived from TGFβ receptortype II (TpRII) or TpRIII; using TGFβ-neutralizing antibodies; or with TpRII or TpRI kinase inhibitors. Furthermore, translation of TGFβ mRNA can be blocked by targeting TGFβ mRNA with antisense oligonucleotides, thus preventing the production of the ligand. Different small-molecule kinase inhibitors against TpRI have been developed to block its kinase activity. Peptide inhibitors against specific TGFβ ligands are also used. Other approaches block the transformation of TGFβ from the latent to the active form. Three molecules are shown that either affect TGFβ signalling indirectly (losartan) or that have an as-yet-unidentified target (tranilast and pirfenidone). All of these approaches decrease the initiation of intracellular receptor signalling pathways, such as phosphorylation of downstream receptor-specific SMADs (R-SMADs), and thereby blunt the transcriptional regulation of target genes. ATI, angiotensin II type 1 receptor; co-TFs, co-transcription factors; FOXH1B, forkhead box protein H1B; LEF, lymphoid enhancer-binding factor; LSKL, Leu-Ser-Lys-Leu peptide; TRX, thioredoxin.

Figure 6

Figure 6. Structures of representative small-molecule inhibitors of TGFβ signalling

Depicted are the molecular structures of a selection of small-molecule inhibitors identified to target the transforming growth factor-p (TGFβ) signalling pathway. SB-431542, LY2157299, SD208 and SM16 are all ATP mimetics that inhibit TGFβ receptortype I (TpRI; also known asTGFBRl) kinase activity. Pyrrole-imidazole polyamide blocks transcription of the TGFB1 gene. Pirfenidone and tranilast have unknown molecular mechanisms of action. Dashed lines denote putative hydrogen bonding with bases in DNA; asterisks indicate positions where hydrogen bonds form with nucleotide residues of DNA within the TGFB1 gene promoter.

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