Targeting Transcription Factors in Cancers

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Bhavuk Garg

Cancers are characterized by uncontrolled growth and failure of differentiation, whereby cells lose their physiological characteristics and acquire malignant phenotypes, also known as neoplastic properties. Examining the distinct properties of cancer cells and their underlying mechanisms are active areas of investigation. Broadly, these properties are summarized as hallmarks of cancer: proliferation, genetic instability, metastasis, cell death resistance, inflammation, angiogenesis, evasion of the immune response, and perturbed energetics. These hallmarks act as a prelude to the development of robust therapeutic interventions against cancers. 

Effective treatment of cancers is a work in progress which is indicated by the advancement of therapeutics from non-specific chemotherapies to targeted inhibitors. Chemotherapeutics such as doxorubicin, paclitaxel, and cisplatin, which target cell proliferation by inhibition of DNA replication and cell division, were the first line of anticancer drugs to be discovered. This was followed by the development of specific kinase inhibitors such as dasatinib, trametinib, and vemurafenib, which target enzymes in constitutively active signaling pathways critical for the malignancy and survival of cancer cells. Recently, advances in mechanistic understanding of the immune system and its evasion by cancer cells have led to the development of immune checkpoint inhibitors such as ipilimumab and nivolumab, which escalate the body’s immune response against cancer cells.

In addition to these classic hallmarks and respective therapeutic strategies, transcription factors form the crux of cancer evolution. Transcription Factors (TFs) regulate cellular characteristics in multicellular organisms by differentially regulating gene expression and serve as effector proteins for signaling pathways that respond to external stimuli to drive cellular growth, differentiation, and death. Dysregulated transcription factor activity is at the heart of the development of neoplastic characteristics in normal cells: TF mutations, gene amplification, and gene fusions constitute major mechanisms of cancer progression. However, unlike enzymes such as kinases, targeting TFs is generally a challenge due to a highly dynamic and disordered structure, and a lack of docking site where drugs can bind. This disordered structure necessitates the requirement of complex formation with their coactivators, as indicated by the myriad assembly of proteins along with TFs on DNA for their optimal activity.

The easiest and earliest TFs to be targeted were nuclear hormone receptors such as the Androgen receptor, Estrogen receptor, and Retinoic acid receptor, which upon binding to their ligands translocate to the nucleus and activate gene transcription. This is because of the presence of binding pockets which can be targeted by drug molecules. Another targeting strategy is leveraging the ubiquitin-proteasome system to degrade TFs.  For instance, researchers discovered that immunomodulatory imide drugs (IMiDs) function by chaperoning the interaction between the Ikaros TFs, which are highly expressed in B cell malignancies and multiple myeloma, and an E3 ligase leading to ubiquitination and degradation of Ikaros TFs which has enabled the use of IMiDs in targeted therapy. Another example is the degradation of p53, a well-characterized tumor suppressor that often is entirely lost or mutated in tumorigenesis. Normally in healthy cells, p53 binds to negative regulator MDM2 which results in its proteasomal degradation and increased cell survival. Inhibition of the protein-protein interaction between p53 and MDM2 is used as a mechanism to elevate p53 levels which results in cancer cell death. 

The development of proteolysis targeting chimeras (PROTACs) is a major step forward for the efficient and specific targeting of TFs via the ubiquitin-proteasome system. PROTACs are bivalent molecules whose ligands simultaneously interact with the protein of interest and an E3 ubiquitin ligase to selectively degrade the target TF – meaning there is no need for an existing protein degradation mechanism like p53-MDM2 to target the TF of interest. Thus, novel PROTAC chimeras can be engineered to target cancer-specific transcription factors in an effort to inhibit cancer-promoting signaling and ameliorate tumor burden.

Persistent research into transcription factors has led to greater insights into their mechanisms of action, binding, and regulatory partners, as well as their dysfunction in cancer settings. In addition, our knowledge of structural challenges in their effective targeting has also improved. Elegant translational application of this understanding and further research of TFs is of critical importance to designing novel specific therapeutics.

Edited by: Gabrielle Dardis

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