STAT3 signaling mediates tumour resistance to EGFR targeted therapeutics

Abstract

Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC). In this mini-review, we specifically focus on the role of the STAT3 signaling axis in providing both intrinsic and acquired resistance to inhibitors of the EGFR. We also focus on STAT3 pathway targeting in an attempt to overcome resistance to anti-EGFR therapeutics.

Introduction

The Epidermal Growth Factor Receptor (EGFR; also referred to as ErbB1 or HER1) is the original member of the ErbB family to be discovered and has become one of the most extensively studied and targeted receptor-tyrosine kinases (Carpenter et al., 1978). Ligand binding (most commonly EGF and TGFα) induces an extended confirmation of the EGFR resulting in the lysine residue (Lys-721) within the EGFR kinase domain becoming more accessible to ATP binding (Burgess et al., 2003, Garrett et al., 2002, Moolenaar et al., 1988, Ogiso et al., 2002). This binding is a critical event required for rapid intrinsic tyrosine kinase activation and auto-phosphorylation of specific tyrosine residues in the intracellular domain of EGFR (Cohen et al., 1982, Ushiro and Cohen, 1980, Wada et al., 1990, Wells et al., 1990), permitting docking of several cellular substrates to the tyrosine kinase domain (Moolenaar et al., 1988, Yarden and Schlessinger, 1987). Subsequently, the recruitment and activation of these molecules, selectively activates downstream signaling networks which include the RAS-RAF-MAPK-ERK1/2 pathway, the PTEN regulated phosphatidylinositol 3-kinase (PI3-K)-AKT-mTOR pathway, Src-Signal transducer and activator of transcription (STAT) family members and the Phospholipase C gamma (PLCγ) signaling pathway (Burgess, 2008) (Fig. 1). In turn, these signaling molecules interact with nuclear transcription factors and cytoskeletal proteins triggering gene transcription of numerous proteins intimately associated with many cellular activities in both development and in the adult organism including proliferation, survival, differentiation, cell polarity, morphology adhesion and migration (Grandal and Madshus, 2008, Wang et al., 2006). Due to its critical regulatory role in many cellular processes, it is no surprise that alterations in EGFR activation including activating mutations and gene amplification (leading to over-expression) has been commonly observed in tumour biopsies compared to normal adjacent tissue. Furthermore, many reports have linked EGFR activation with increased tumour invasiveness and tumour metastatic potential (Neal et al., 1985, Sainsbury et al., 1987, Abbott and Pratt, 1991, Damstrup et al., 1998, Johnson et al., 1997, Khazaie et al., 1993, Parker et al., 1998, Radinsky et al., 1995, Toi et al., 1991). Indeed breast, bladder, ovarian, oesophageal, non-small cell and squamous cell lung carcinoma (NSCLC), colon, head and neck and brain cancers have all been shown to over-express the EGFR (Neal et al., 1985, Sainsbury et al., 1987, Bartlett et al., 1996, Ekstrand et al., 1991, Hendler and Ozanne, 1984, Hollstein et al., 1988, Ishitoya et al., 1989, Libermann et al., 1985, Veale et al., 1987), and this over-expression has often been correlated with poorer overall survival outcomes (Neal et al., 1985, Sainsbury et al., 1987, Bartlett et al., 1996, Veale et al., 1987, Jaros et al., 1992, Mayer et al., 1993).

These studies, conclusively demonstrate that EGFR activation is critical for tumour development and progression led to the rationale behind generating agents that target and inhibit the EGFR. Subsequently, several anti-EGFR therapeutic agents have successfully entered clinical trials and have been FDA-approved for numerous cancer types (summarised in Table 1). Despite being commonly used in the clinic, therapies based around the use of cetuximab, panitumumab, gefitinib, erlotinib, lapatinib and afatinib only result in moderate increases in the overall survival of cancer patients. The presence of pre-existing intrinsic or de novo resistance mechanisms and the ability of tumours to develop or acquire resistance to these inhibitors are common and occur through several proposed mechanisms. Alterations in the level of EGFR expression, copy number and mutations in both the ectodomain and the intracellular kinase domain have all been shown as potential avenues of resistance to anti-EGFR therapies in various cancer types. Indeed, the “gatekeeper” EGFR T790M mutation that renders NSCLC patients that expresses this mutation refractory to gefitinib or erlotinib treatment has been extensively described and is routinely screened for in patient biopsies to assist in treatment management decisions (Arcila et al., 2011, Kobayashi et al., 2005, Maheswaran et al., 2008, Pao et al., 2005, Rosell et al., 2011, Sequist et al., 2011, Tartarone and Lerose, 2015). Differential expression and mutations in the other ligands and ErbB receptors and alterative ligand and receptor signaling pathways have also been implicated in correlating with clinical response to anti-EGFR therapy. These include mutations to molecules that confer constitutively active downstream signaling including RAF, RAS and PI3-K, with the presence of K-RAS mutations guiding the decision to not use cetuximab or panitumumab in metastatic colorectal cancer (mCRC) patients (Bokemeyer et al., 2009, De Roock et al., 2010, Douillard et al., 2013, Karapetis et al., 2008, Lievre et al., 2006, Loupakis et al., 2009). However, we will not discuss these molecular mechanisms of tumour resistance to anti-EGFR therapy in this mini-review which are extensively reviewed elsewhere (Bertotti and Sassi, 2015, Dienstmann et al., 2015, Landi and Cappuzzo, 2014, Niederst and Engelman, 2013, Van Emburgh et al., 2014), but rather focus on the less studied resistance mechanisms driven by the STAT3 signaling pathway.