Targeting TGF-Β Signaling for Therapeutic Gain
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Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Targeting TGF-b Signaling for Therapeutic Gain Rosemary J. Akhurst Department of Anatomy and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158-9001 Correspondence: [email protected] Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types. he three transforming growth factor bs titude of TGF-b-induced tumor promoting ef- T(TGF-bs), TGF-b1, -b2, and -b3, are closely fects modulate the tumor cells directly through related ligands that act on most cells types of the enhancement of tumor cell invasion and metas- body and have pleiotropic activities. Expression tasis, and induction and maintenance of cells of TGF-b1 is activated by tissue perturbations with tumor initiating properties, sometimes that induce cellular stress, such as cell prolifera- termed cancer stem-like cells (CSCs). Another tion and inflammation, and the induced ligand major site of protumorigenic TGF-b activity acts to reestablish homeostasis, acting as part is the tumor microenvironment (TME). Here, of a negative feedback circuit (Cui et al. 1995; TGF-b induces extracellular matrix (ECM) Akhurst et al. 1988; Li and Flavell 2008). In many deposition, myofibroblast differentiation, and diseased states, however, including fibrosis and angiogenesis, and suppresses both the innate cancer, TGF-b expression is chronically and ab- and adaptive immune systems. This results in a errantly elevated (Derynck et al. 1987; Fowlis feed-forward circuit of interactions between the et al. 1992; Gorsch et al. 1992; Walker and Dear- tumor and TME, which furthers tumor progres- ing 1992; Bellone et al. 1999, 2001). What is sion and results in aggressive, invasive, and met- more, responses to the ligand are altered toward astatic tumors that can be desmoplastic, with events that promote disease progression (Der- elevated intratumoral tension and high intersti- ynck et al. 2001; Roberts and Wakefield 2003). tial fluid pressure (IFP), all features that may be This is especially true in cancer, in which a mul- ameliorated by TGF-b signaling blockade. Over Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a022301 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press R.J. Akhurst the last two decades this signaling pathway has THE TGF-b SIGNALING PATHWAY therefore become a target for drug development, both for fibrosis and for oncology (Akhurst and The TGF-b family is comprised of more than Hata 2012). This review will focus on oncology 30 different homo- and heterodimeric pleiotro- applications, because there has been a rebirth of pic ligands encoded by 33 different genes. The interest in TGF-b blockade for cancer immuno- family includes TGF-bs, bone morphogenetic therapy with the clinical successes in this rapidly proteins (BMPs), GDFs (growth and differenti- expanding field. Drug development for fibrosis ation factors), activins and inhibins, nodal, and applications, other than that related to oncology, anti-Mu¨llerian hormone (AMH) (Schmierer is not addressed because this topic has been re- and Hill 2007). Each of these ligands binds to viewed previously (Akhurst and Hata 2012). and activates signaling through heteromeric Moreover, treatment of chronic fibrotic condi- combinations of dual specificity kinase receptors tions by current anti-TGF-b signaling drugs that phosphorylate and activate downstream may be challenging because of the need to define Smad and non-Smad signaling components in a therapeutic window and dosing regimen be- a receptor kinase-dependent or independent tween efficacy and side effects. This review will manner (Fig. 1) (Derynck and Zhang 2003; Sor- cover the basics of TGF-b signaling and its bio- rentino et al. 2008). There can be considerable logical activities relevant to oncology, present a cross talk between intracellular signaling path- summary of pharmacological TGF-b blockade ways of the different TGF-b subfamilies, both strategies, and give an update on preclinical and downstream from and upstream of their respec- clinical trials for TGF-b blockade in a variety of tive receptors (Ray et al. 2010; Gro¨nroos et al. solid tumor types. 2012; Peterson and O’Connor 2013). In disease TGF-β TNF Wnt TGF-α FGF EGF Smad3 Non-Smad pathways PI3K P Ras-Erk MAPK Smad3 Smad4 Rho-JNK Modification of Smad P RhoA-ROCK transcriptional output Smad3 TAK1-p38 MAPK P Context-dependent TF Smad3 Transcriptional output Figure 1. Context-dependent transforming growth factor b (TGF-b) signaling outputs arise from pathway interactions. Schematic of TGF-b signaling via the canonical Smad pathway (center) or noncanonical signaling pathways (right). Modification of Smad transcriptional output (left) may be by posttranslational modification of Smads, such as by linker phosphorylation byextracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK) or by the presence or activation status of interacting transcription factors that are regulated by other stress and other growth factor signaling pathways. EGF, Epidermal growth factor; FGF, fibroblast growth factor; TNF, tumor necrosis factor; PI3K, phosphoinositide 3-kinase; JNK, c-Jun amino-terminal kinase. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a022301 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Targeting TGF-b Signaling for Therapeutic Gain states, ablation of signaling from one ligand sociated peptide (LAP), is cleaved from the subtype may interfere with the signaling output carboxy-terminal mature peptide by a subtili- from others in either a positive or negative man- sin-like proprotein convertase, furin, but re- ner, with one of the finest examples being found mains noncovalently associated with the mature through human genetics (Hatsell et al. 2015). homodimeric ligand (Annes et al. 2003). Di- Chronic versus acute inhibition of TGF-b sig- meric LAP encapsulates the mature dimeric naling may result in quite different outcomes peptide within a cage-like structure, keeping it (Connolly et al. 2011), because negative feed- in an inactive state that facilitates spatial and back loops have evolved to keep this important temporal regulation of storage, delivery, and ac- signaling pathway in equilibrium within the cell tivation (Shi et al. 2011). On the outer surface of (Fig. 1). this “cage,” one of the two LAP arms also binds The three bona fide TGF-b ligands are dis- covalently to a LTBP (latent TGF-b-binding tinguished from other ligands of this family by protein), which is a large ECM component extensive sequence homology and their unique that anchors latent TGF-b within the ECM ability to bind and signal via the TGF-b receptor rather than permitting free diffusion within type II, TbRII. When the homodimeric ligands the tissue (Munger et al. 1997; Ota et al. 2002; bind to the extracellular domain of TbRII, het- Annes et al. 2003). LTBP noncovalently binds ero-oligomerization of the two canonical recep- fibrillin (Chaudhry et al. 2007), mutations of tors, TbRI and TbRII, causes a conformational which are causative for Marfan syndrome (Rob- change in the receptor complex that results in inson et al. 2006). Dimeric LAP also binds non- phosphorylation, and subsequent activation, of covalently to cell surface integrins, particularly the type I receptors by the type II receptors (Shi integrins b1, b6, and b8, which can bind latent and Massague´ 2003). Activation of TbRI leads TGF-b1 and b3 via an RGD site within the cor- to signal propagation through the well-charac- responding LAP domains (Munger et al. 1999; terized Smad-dependent canonical pathway Annes et al. 2004; Yang et al. 2007; Arnold et al. and/or Smad-independent noncanonical path- 2014). This interaction results in TGF-b activa- way(s) (Derynck and Zhang 2003). Cross talk tion, triggered by the molecular tension result- between Smad and non-Smad signaling path- ing from physical stretch between LAP-integrin ways can directly modify Smad transcriptional binding at the cell surface and LAP–LTBP an- output, as can interaction between TGF-b and chorage to the ECM (Yang et al. 2007; Shi et al. other growth factor signaling pathways. Smads, 2011; Dong et al. 2014; Mi et al. 2015). Proteo- forexample, can be phosphorylated within their lytic cleavage of the amino-terminal motif of central “linker” domain by other kinases, such LAP can also activate TGF-b by releasing the as the extracellular signal-regulated kinase (Erk) entrapped active homodimer from its latent mitogen-activated protein kinase (MAPK) path- protein cage (Dong et al. 2014). On the surface way (Kretzschmar et al. 1999), c-Jun amino- of T cells and platelets, the transmembrane pro- terminal kinase (JNK) MAPK pathway (Engel tein glycoprotein A repetitions predominant et al.