Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer-related death and despite efforts to improve treatment options, the overall 5-year survival still remains poor at 15% (Torre, 2016). As in other malignancies, novel systemic therapies for the treatment of lung cancer have shifted from cytotoxic chemotherapy to molecularly targeted agents. Over the past decade, there has been a concerted effort to identify driver mutations or translocations that could be targeted. To date, one of the most successful classes of novel targeted agents for the treatment ofnon-small cell lung cancer (NSCLC) have inhibited the epidermal growth factor receptor (EGFR) pathway. Initially, EGFR inhibitors entered clinical practice for the treatment of advanced NSCLC in a molecularly unselected NSCLC population (Shepherd, 2005), with modest clinical benefit, driving efforts to identify biomarkers to define subpopulations of patients with NSCLC most likely to benefit from these agents. These efforts have led to extraordinary advances in the treatment of NSCLC for subsets of patients. This chapter will review the status of the predictive biomarker research for the EGFR inhibitors that are currently in clinical use for the treatment of NSCLC.
The Epidermal Growth Factor Receptor Family
The epidermal growth factor receptor (EGFR) family consists of four members: EFGR, human epidermal growth factor receptor-2 (HER2), HER3, and HER4. All members of the EGFR family contain an extracellular ligand-binding region, a membrane spanning region and cytoplasmic region, which possesses tyrosine kinase activity. The binding of a ligand to the receptor leads to the formation of either homo or heterodimers between members of the epidermal growth factor receptor family and activation of tyrosine kinase activity (Yarden, 2001). This leads to the binding of adenosine triphosphate (ATP) and phosphorylation of the cytoplasmic component of the kinase. This phosphorylation event allows adaptor proteins to interact with the receptor and initiate the downstream signaling pathways, Fig. 6.1 (Yarden, 2001). Without ligand, the EGFR receptor is found in a closed conformation with the dimerization interface blocked. Unlike EGFR, HER2 has a different extracellular region and has a fixed conformation which results in permanent exposure of the dimerization domain (Garret, 2003). In addition, HER2 is unique among the receptor family in that it binds none of the potential EGF ligands. As a result, it appears that its primary role in the pathway is to form heterodimers with the other receptors (Graus-Porta, 1997). HER3 also plays a distinct role in the HER family signaling network. Although it is kinase inactive and therefore incapable of initiating downstream signaling pathways on its own, HER3 can dimerize with other receptors, particularly HER2, for potent cellular signaling.
Signal Transduction Pathways Controlled by the Activation of EGFR 189
Figure 6.1 The EGFR pathway. EGFR signaling commences with the binding of ligand (e.g., EGF, TGF-a) to the EGFR receptor. This leads to dimerization, with one part being EGFR and the other part being one of EGFR, HER2, ErbB3 or ErbB4. Dimerization leads to activation of the intracellular tyrosine kinase domains through autophosphorylation. Through docking proteins, both the RAS/RAF/MAPK pathways and PI3K/Akt pathways are activated. Activation of these pathways leads to cell cycle progression, increased cell division, increased cell survival and increased probability of metastasis. EGFR also activates the STAT protein family in the cytosol. This leads to translocation into the nucleus and further transcription regulation.
Signal Transduction Pathways Controlled by the Activation of EGFR
A schematic of the signal transduction pathways under the control of EGFR is shown in Fig. 6.1. Overall, two major pathways are involved: the RAS-RAF-MAPK (Ras) pathway and the phosphoinositol-3-phosphate-Akt (PI3K) pathway. For the Ras pathway, activated EGFR recruits Ras and initiates activation through the exchange of guanine diphosphate (GDP) to guanine triphosphate (GTP) (Lurje, 2009). This leads to signal transduction and transcription of genes controlling cycle-cycle progression and cellular proliferation (Hill, 1995). Unlike the Ras pathway, EGFR activation of the PI3K
190 I Predictive Biomarkers for EGFR Agents in Non-Small Cell Lung Cancer
pathway requires only the presence of HER3 and is not dependent on adaptor proteins (Yarden, 2001). Interaction with PI3K leads to phosphorylation of phosphatidylinositol 4,5-diphosphate, resulting in phosphatidylinositol 3,4,5-triphosphate. This molecule then activates Akt and other downstream effector pathways controlling cell proliferation and survival (Vivanco, 2002). This results in increased cell growth, apoptosis resistance, increased tumor invasion and cell migration (Stokoe, 1997).
In addition to the above pathways, EGFR has the ability to regulate signal transducers and activators of transcription (STAT) and sarcoma kinase (Src) pathways through the Janus kinase (JAK). STAT proteins have been implicated in oncogenesis and tumor progression while Src can cause increased EGFR signaling and resistance to EGFR-targeted therapy (Yu, 2004; Leu, 2003).