Oncogenic Molecular Pathways: Mechanisms, Mutations and Inhibitors

Review Article

Ann Hematol Oncol. 2016; 3(8): 1108.

Oncogenic Molecular Pathways: Mechanisms, Mutations and Inhibitors

Ali A1,2 and Li X1,2.*

¹Shanghai Key Laboratory of Regulatory Biology, East China Normal University, China

²Department of Molecular and Cellular Biology, Baylor College of Medicine, USA

*Corresponding author: Xiaotao Li, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

Received: July 26, 2016; Accepted: September 19, 2016; Published: September 21, 2016

Abstract

Oncogenic signaling pathways play crucial role in the development and progression of both solid tumors and hematological malignancies. It is well established that how these oncogenic signaling exerts its mode of action and how the key mutations in these signaling pathways lead to cancer development. Oncogenic signaling promote cancer progression by regulating growth, proliferation, cell cycle progression and apoptosis in both solid and hematological cancers. Activation of key oncogenic signaling is associated with drug resistance in multiple cancers, which is one of the main challenge to treat cancer patients effectively with chemotherapeutic agents. To date, several inhibitors are developed to target the key signaling molecules and mutations in these oncogenic signaling pathways to suppress tumorigenesis. Cell surface receptors and their cognate ligands play crucial role in the activation of cellular signaling, which subsequently enhance cancer metastasis and EMT-like features in cancer cells. Oncogenic signaling mainly exerts its mode of action via phosphorylation and activation of different transcription factors, and thereby control the expression of target gene, which are involve in tumorigenesis. Depletion or inhibition of key kinases in these oncogenic signaling pathways has been shown to suppress cancer cell growth and is associated with induction of apoptosis. Here, this review is focus on key oncogenic signaling pathways, their mutations and inhibitors in both solid tumors and hematological malignancies.

Keywords: Oncogenic signaling; Cancer progression; Chemotherapeutic agents; Growth factors; Genetic mutations; Leukemia

List of Oncogenic Molecular Pathways

Introduction

Tumor microenvironment has been shown to play crucial role in cancer cell growth, proliferation, DNA synthesis and survival and promotes epithelial mesenchymal transition (EMT)-like features and metastasis in both solid tumor and leukaemogenesis [1]. Several different types of inhibitors and cytotoxic drugs has been developed to suppress the growth and induce the apoptosis of cancer cells within tumor microenvironment. Genome instability, amplification, copy number alteration and mutations in key proteins play crucial role in cancer development, progression, EMT and metastasis [2]. Amplification of oncogenic proteins is key to tumorigenesis. Once, the amplification of oncogenic proteins occur, then its play a dominant role in cancer cells by suppressing the function of tumor suppressor genes and thereby promote cancer cell growth and proliferation. Protein-protein interaction play important role in the suppression function of tumor suppressor proteins. Oncogenic proteins mostly block the function of tumor suppressor proteins by interacting with key domain and region with tumor suppressor proteins and subsequently enhance cancer cell growth. Most of the oncogenic proteins serve as a transcription factors and they binds to the promoter regions of tumor suppressor genes and thereby repress their expression. In some cases, oncogenic proteins forms a large transcriptional complex, which also include co-activators and co-repressors, to suppress the function of tumor suppressor gene. In some cases, competition occurs among cancer-related proteins for binding to the promoters of their common target genes. In some solid tumors, oncogenic proteins co-amplification occurs, in which one of the protein play a dominant role to control cancer cell growth, proliferation and survival.

Both solid tumors and hematological malignancies show heterogeneity. The contain activation, amplification and mutations of several genes within the same tumor. Due to this heterogeneous nature of tumors, it is also challenging to suppress the cancer cell growth with different inhibitors, cytotoxic agents and monoclonal antibodies. Epigenetic changes has also been shown to play very important role in cancer progression and survival. Several studies linked chromatin modification, methylation and acetylation with cancer suppression or progression. The function of different coactivators and co-repressors in cancer cell in context-dependent.

The Ras/Raf/MEK/ERK pathway

Multiple growth factors proteins and cytokines binds to their target receptors, which is mainly express on cell surface, and triggers the activation of downstream Mitogen activated protein kinases (MAPK) that mainly include Ras/Raf/MEK/ERK signaling cascade [1]. This signaling cascade in turn activates and phosphorylates a network of transcription factors, which translocate into nucleus to control the expression of different genes that are involve in cell growth, invasion, migration and survival [2]. Several important proteins such as phosphatases, kinases and scaffold proteins play key role in the activation and amplification of MAPK regulated Ras/ Raf/MEK/ERK-dependent signaling pathway in cancer cells (Table 1). Importantly, genetic mutations and instability in key molecules of these signaling promote tumorigenesis, invasion and metastasis [3]. Mechanistically, Activation of MAPK occurs via association of a growth factor receptor (GFR) with Src homology 2 domain containing protein (Shc). Shc play crucial role in the recruitment of growth factor receptor-bound protein 2 (Grb2) proteins and the son of seven less (SOS) homolog protein to the cell surface receptor complex and thereby exchange occurs between GDP and GTP [4] (Figure 1). Moreover, it has been shown that insulin receptor substrate (IRS) also promote Ras signaling activation via binding with Grb2. To date, K-RAS, N-RAS and H-RAS, these three different types of Ras proteins exist. These three different proteins play important role in cancer cell in context-dependent manner [5]. It is well documented that GTPase activating proteins (GAPs) suppress the Ras signaling pathway. GAPs such as p120GAP and NF1promote the GTPase activity and thereby convert GTP to GDP to turn off Ras signaling pathway [6,7]. Once the Ras signaling becomes activated, then it activates and phosphorylate Raf protein to further activate the downstream signaling of MAPK. Ras mediated Raf-1 activation is dependent on calcium/calmodulin-dependent protein kinase II (CaMK-II), which phosphorylates Raf-1 at S338 [8]. B-RAF, RAF-1 (c-RAF) and A-RAF are the three different types of Raf, which exists to date. PP2A has been shown to play important role in inactivation of Raf-dependent signaling via dephosphorylation [9]. Furthermore, activated Raf phosporylate mitogen-activated protein kinase- 1/2(MEK1/2). In turn, activated MEK-dependent signaling pathway further phosphorylate and activates extracellular signal regulated kinases 1/2 (ERK1 and 2) by targeting T /Y residues [10] (Figure 1). Kinase suppressor of Ras (KSR) has been shown to suppress the MAPK-dependent signaling by targeting MEK via phosphorylation. Moreover, it is well established that p21-activating kinases (PAK) and Rac (Ras related gene) proteins also phosphorylate and activates MEK/ERK-dependent signaling in cancer cells. The dual specificity phosphatases DUSP (MKPs) act as negative regulator of MAPK signaling by inhibiting ERK1/2 signaling pathway in cancer cells [11]. Activated ERK1/2 signaling, in turn, phosphorylate and activate p90 Ribosomal six kinase-1 (p90Rsk1), MAPK signal integrating kinases (Mnk1/2), focal adhesion kinase (FAK) and myosin light polypeptide kinase (MLCK). Post-translational modification play important role in the activation of these target proteins by ERK1/2- dependent signaling [12]. ERK1/2-dependent signaling activates different transcription factors such as ETS, ATF-2, CREB and AP-1 to translocate into the nucleus. In nucleus, these transcription factors interact with different co-activators or co-repressors to regulate the target gene expression. These transcription factor mainly promote the expression of tumor associated genes and on another hand suppress the expression of tumor suppressor proteins to promote growth, invasion, proliferation, metastasis. Activated ERK1/2 signaling also has been shown to promote the expression of EMTrelated transcription factors such as TWIST1, SLUG, SNAIL and ZEB [13,14].