Targeting the transforming growth factor-beta signaling pathway in human cancer

Abstract

The transforming growth factor-ss (TGF-beta) signaling pathway plays a pivotal role in diverse cellular processes. TGF-beta switches its role from a tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that the Smad-dependent pathway is involved in TGF-beta tumor-suppressive functions, whereas activation of Smad-independent pathways, coupled with the loss of tumor-suppressor functions of TGF-beta, is important for its pro-oncogenic functions. TGF-beta signaling has been considered a useful therapeutic target. The discovery of oncogenic actions of TGF-beta has generated a great deal of enthusiasm for developing TGF-beta signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-beta-induced tumor suppressor functions but also responsive to the tumor-promoting effects of TGF-beta. TGF-beta pathway inhibitors, including small and large molecules, have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here, we focus on the mechanisms of signaling and specific targets of the TGF-beta pathway that are critical effectors of tumor progression and invasion. This report also examines the therapeutic intervention of TGF-ss signaling in human cancers.

Figure 1. The TGF-β signaling through Smad-dependent and Smad-independent pathways

TGF-β receptor signals through multiple signaling cascades. TGF-β activates Smad and non-Smad pathways. The ligand-activated TGFβRI and TGFβRII receptor complex recruits and phosphorylates the receptor specific R-Smads. The R-Smads are presented to the TGFβRI by a membrane-bound protein, SARA. R-Smad proteins are cytoplasmic molecules which, after receptor activation, associate with Co-Smad. Hetero-oligomeric complex of R-Smad-Co-Smad translocates to the nucleus and binds to specific DNA sequence and interacts with transcription factors (TF) and Co-factors (CF) to regulate transcription. R-Smads and Co-Smad shuttle between nucleus and cytoplasm. The pathway is negatively regulated by the I-Smads which binds activated TGFβRI, thereby preventing phosphorylation of R-Smads, or recruits the E3 ubiquitine ligases, Smurf1 and Smurf2 to induce proteosomal degradation of the R-Smads. STRAP interacts with TGFβRI and TGFβRII and with I-Smad, thus stabilizing the interaction of I-Smad with the receptor complex. Activation of the epidermal growth factor (EGF) receptor and other tyrosine kinase receptors, interferon (IFN)-γ signaling, and activation of NF-κB by tumor-necrosis factor (TNF)-α, also induce I-Smad expression, leading to inhibition of TGF-β signaling. Although the mechanism of activation of non-Smad pathways by the receptor complex remains largely unknown, these pathways are known to be involved in the pro-oncogenic responses to TGF-β in cooperation with or without Smad pathway. The activated receptor complex activates non-Smad signaling pathways, such as PI3K/Akt, Rho/Rac GTPases and Ras/MAPK and TAK1/MEKK1. TAK1 (TGF-β activated kinase 1) may mediate TGF-β effects with respect to the activation of distinct MAP kinase pathways (JNK, p38). TGF-β also induces activation of the Cdc42 GTPase which stimulates p21 activated kinase (PAK) downstream from Rac and Cdc42. TGF-β activation of PP2A, that inhibits S6K activity through the mTOR/FRAPPP2A-S6K pathway, mediates Smad-independent growth suppression. SBE: Smad binding element and TBE: Transcription factor binding element.

Figure 2. TGF-β signaling pathway inhibitors that are currently under development for potential cancer therapy

The TGF-β signaling pathway offers many different avenues for therapeutic intervention, each of which offers advantages and drawbacks. Current therapeutic approaches for modulating TGF-β signaling involve antagonism of TGF-β ligand binding to the heteromeric receptor complex with isoform-selective antibodies as large molecule inhibitors, such as metelimumab (for TGF-β2) and lerdelimumab (for TGF-β2/3) from Genzyme, and pan-TGF-β antibodies such as GC-1008 (Genzyme), ID-11 (Genzyme), SR-2F (NCI/NIH) and 2G7 (Genentech) antibodies, or soluble TGFβRII receptor fusion proteins (Biogen). Alternatively, the intracellular inhibition of the TGFβRI kinase can be achieved with small molecule inhibitors, such as SB431542 and SB505124 from GlaxoSmithKline; LY580276, LY550410, LY364947, LY573636 and LY2157299 from Eli Lilly; SD093 and SD208 from Scios. Other inhibitors for TGF-β receptor kinase are NPC30345 (Scios), Ki-26894 (Kirin brewery), SM16, A-83-01 (Kyoto Pharma), SX-007 (Scios) and IN-1130 (In2Gen), and dual inhibitors of both the TGFβRI and TGFβRII kinases, such as LY2109761 (Eli Lilly). Alternatively, expression of TGF-β isoforms can be affected by antisense technology targeting mRNA sequence-specific degradation, such as AP-12009 and AP-11014 which were developed by Antisense Pharma and targeted to TGFβII and TGFβI, respectively. SIS3 is a selective chemical inhibitor of Smad3 activation and Smad3-mediated DNA binding and gene expression.