Gene expression (quantitative assessment) of cell surface receptors



Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is frequently overexpressed in non‐small cell lung cancer (NSCLC). These receptors play an important role in tumour cell survival and activated phosphorylated EGFR results in the phosphorylation of downstream proteins that cause cell proliferation, invasion, metastasis, and inhibition of apoptosis. Expression appears to be dependent on histological subtypes, most frequently expressed in squamous cell carcinoma but also frequently expressed in adenocarcinomas and large cell carcinomas. A much more important issue for patients with NSCLC is whether a relationship exists between EGFR expression and survival benefit with EGFR inhibitor therapy. This might disadvantage patients with negative or low EGFR expression who might benefit from EGFR inhibitor treatment as most trials involving EGFR blockade preclude patients with no EGFR protein expression. Two EGFR inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), have been approved for use as second line or third line treatment in advanced NSCLC.

  • HER2/ERBB2

HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that in humans is encoded by the ERBB2 gene . Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer and in recent years it has evolved to become an important biomarker and target of therapy for the disease. Amplification or over-expression of the ERBB2 gene occurs in approximately 30% of breast cancers. It is strongly associated with increased disease recurrence and a worse prognosis. Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer. HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis. HER2 is the target of the monoclonal antibody Herceptin which is effective only in cancers where HER2 is over-expressed. HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for Herceptin therapy. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to Herceptin therapy.

  • ERBB3

ErbB3 is a member of the EGF family of receptors. Signaling through ERBB3 is mediated by heregulin (HRG) and epidermal growth factor receptor (EGFR) ligands like betacellulin (BTC). ERBB3 is a critical mediator of prosurvival signaling through PI3K/AKT activation and potentially also through activation of other pathways involved in proliferation, differentiation, and survival of cancer cells.Signaling through ErbB3 is a major mechanism by which cancer cells acquire resistance to targeted therapies (including EGFR and HER2 inhibitors), chemotherapies, and, potentially, radiotherapy. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors.

Schoeberl B, Faber AC, Li D, et al. Cancer Res. 2010;70:2485-2494.

  • C-ΜΕΤ

c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR). Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Because of its ubiquitous role in cancer cells, the MET axis has been seen as an attractive target for cancer therapy. Over the last four years, more than 10 anticancer agents targeting different aspects of MET signaling via different mechanisms have been introduced into the clinic. The majority of MET inhibitors are still in late phase I and phase II trials, but at least three compounds, tivantinib, onartuzumab, and cabozantinib, are in phase III trials in lung cancer and medullary thyroid cancer. It should also be noted that MET is expressed not only in tumor cells and endothelial cells, but also in osteoblasts (bone-forming cells) and osteoclasts (bone-removing cells). The MET pathway is abnormally regulated in a wide range of human cancers, including the most common epithelial cancers such as breast, colorectal, lung, pancreatic, hepatic, and ovarian cancers. MET inhibitors remain a very promising class of compounds for cancer therapy.

  • RET

  • C-KIT

Proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a protein that in humans is encoded by the KIT gene. CD117 is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrowAltered forms of this receptor may be associated with some types of cancer. Activating mutations in this gene are associated with gastrointestinal stromal tumors , mast cell disease, melanoma, acute myeloid leukemia, while inactivating mutations are associated with the genetic defect piebaldism . CD117 is a proto-oncogene , meaning that overexpression or mutations of this protein can lead to cancer. c-kit is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-kit gene on carcinogenesis. Gain-of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. STI571 is a small molecule that selectively inhibits the enzymatic activity of several tyrosine kinases, such as the growth factor receptor with tyrosine kinase activity, a product of the c-kit gene. The physiological ligand is the cytokine stem cell factor (SFC), also called mast cell growth factor or Steel factor. Mutations of c-KIT that cause constitutive activation of the tyrosine kinase function of c-KIT are detectable in most gastrointestinal stromal tumours (GISTs).

  • PDGFRα

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferationcellular differentiationcell growthdevelopment and many diseases including cancer. Alpha-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRA gene . It is overexpressed in a subset of solid tumors and therefore is the target of drugs inhibiting this function such as imatinib mesylate (Gleevec).

  • IGF1R

IGF1R plays important roles in proliferation, apoptosis, angiogenesis, and tumor invasion. It has been reported that its expression level is related to resistance to several targeted therapies. Histology and in situ hybridization have revealed that IGF1R was significantly up-regulated at the protein and mRNA level in many types of cancer, including breast, prostate, colon, pancreatic, lung and thyroid cancer. In addition, down-regulation of IGF1R was associated with decreased tumor growth in various xenograft tumor models. Because of the importance of IGF1R in cancer development, many therapeutic agents such as antibodies and tyrosine kinase inhibitors have been developed to target/inhibit IGF1R and several of these agents are currently in clinical investigation.

  • VEGFR2

VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Breast cancer cell lines and primary breast cancers can express vascular endothelial growth factor (VEGF), or its receptors, and increased VEGF expression in breast cancers is associated with tumor progression and increased risk of recurrence. Although the antiangiogenic effects of agents targeted against VEGF have been emphasized in cancer, tumors that express both VEGF and its receptors can participate in autocrine/paracrine feedback loops, and the specific effects of anti-VEGF agents on these autocrine loops can be studied in vitro, where angiogenesis is not at issue. HER2 can regulate VEGF production in human breast cancer cell lines, and VEGF levels are correlated with HER2 expression in primary breast cancers. EGFR can also up-regulate the expression of VEGF in cancer cell lines, and inhibition of EGFR activity reduces VEGF production and angiogenesis in vivo. Given that HER2 and EGFR can heterodimerize to initiate signal transduction, and that each can regulate VEGF production, it would seem reasonable to compare the effects of inhibition of EGFR, HER2, and VEGF, individually and in combination, in breast cancer cell lines.

  • NRP2
  • TGFβR
  • AR
  • TROP2
  • IL17BR

Interleukin-17 receptor B is a protein which in humans is encoded by the IL17RB gene. It has been observed at high levels in individuals who are submited with treatment for cardiac fibroblasts and in certain tissues, such as haematopoietic, bone marrow, thymus, spleen and tissue. The IL-17BR exists also in normal conditions and in low levels in small intestine, and in lung tissues.

  • CXCR4

CXC chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the CXCR4 gene. In addition, CXCR4 can also be found on vascular endothelial cells and neuronal / nerve cells. Drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream as peripheral blood stem cells. CXCR4 is one of the best studied chemokine receptors, which selectively binds to the CXC chemokine stromal cell-derived factor 1 (SDF-1), also known as CXCL12 (Fredriksson et al., 2003). CXCR4 is exclusively expressed in the cytoplasm, but not expressed in the nuclear and membrane of renal tumor cells. CXCR4 is expressed in a broad range of tissues, including immune and the central nervous systems, but lowly or absently expressed in many normal tissues including breast and ovary. High expression of CXCL12 has been discovered in lymph node, bone marrow, liver, lung and brain, which are common sites of metastasis from various malignant cancers.

The chemokine receptor CXCR4 is emerging as an important target in cancer growth, metastasis, relapse and resistance to therapy. While combination chemotherapy has lead to modest improvements in outcome, the 5 y overall survival for SCLC remains at 5%. As in most cancers, early stage lung cancer can often be controlled with locally directed therapy including radiation and surgery; it is the almost inevitable development of metastatic disease that leads to a high mortality rate in SCLC. The identification of several tyrosine kinase receptors important in the pathogenesis of lung cancer, including epidermal growth factor receptor (EGFR), has lead to the development of targeted therapies, including erlotinib and cetuximab. However, while these EGFR targeted agents have improved survival in patients with NSCLC, therapy for advanced stage SCLC relies largely on response to cytotoxic chemotherapy. Therefore identifying distinct biochemical pathways of metastasis and chemotherapy resistance in SCLC may lead to novel therapeutic approaches and improve survival in SCLC patients. Recently, a novel CXCR4 antagonist, AMD070 (Genzyme Corporation), was shown to be well tolerated in healthy volunteers12 and in combination with ritonavir (antiviral and protease inhibitor) in patients with HIV.69 A dose-dependent elevation in white blood cell count was observed as a pharmacodynamic marker of anti-CXCR4 activity in HIV patients. In addition, other CXCR4 inhibitors are currently being tested in patients with HIV and cancer in Phase I and II clinical trials.70 BKT140 (Biokine Therapeutics) is a highly selective modified peptide CXCR4 antagonist being tested in a Phase I/IIA trial in myeloma patients. TG-0054 (TaiGen Biotechnology Co., Ltd.) is a CXCR4 antagonist currently being evaluated in a randomized, double-blind, placebo-controlled, sequential ascending single intravenous dose study to assess safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers.

The CXCR4/CXCL12 pathway plays an important role in SCLC proliferation, metastasis, resistance to treatment and relapse. This pathway may provide a novel therapeutic approach by targeting tumor progression and spread as well as the chemoprotective tumor microenvironment. Innovative research in pathways of metastasis and chemotherapy resistance is essential to understanding the pathogenesis of small cell lung cancer and developing targeted treatment approaches.

  • ITGA4