THE PHARMACOGENOMICS OF EGFR-DEPENDENT NSCLC: PREDICTING AND ENHANCING RESPONSE TO TARGETED EGFR THERAPY

The introduction of tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) inhibitors to the clinic has resulted in an improvement in the treatment of non small cell lung cancer (NSCLC). However, many patients treated with EGFR TKIs do not respond to therapy. The burden of failed treatment is largely placed on the healthcare field, limiting the effectiveness of EGFR TKIs. Furthermore, responses are hindered by the emergence of resistance. Thus, two questions must be addressed to achieve maximum benefit of EGFR inhibitors: How can patients who will benefit from EGFR TKIs be selected a priori? How can patients who respond achieve maximal benefit? To answer these questions, two hypotheses were formed. First, the EGFR-dependent phenotype, which is displayed by the tumors cells of those patients who respond clinically to EGFR TKIs, can be captured by genomic profiling of NSCLC cell lines stratified by sensitivity to EGFR TKIs. This gene signature may be used to predict the outcome of EGFR TKI therapy in unknown samples. Secondly, the predictive signature of response to EGFR TKI could provide insights into the underlying biology of the phenotype of EGFR-dependency. This information could be exploited to identify inhibitors which could be combined with EGFR inhibitors to elicit a greater effect, thereby minimizing resistance. The work herein describes the testing of these hypotheses. Pharmacogenomics was utilized to define a signature of EGFR-dependency which effectively predicted response to EGFR TKI in vitro and in vivo. Furthermore, the signature was analyzed by bioinformatic approaches to identify the RAS/MAPK pathway as a candidate target in EGFR-dependent NSCLC. The RAS/MAPK pathway regulates expression and activation of EGF-like ligands. Furthermore, the RAS/MAPK pathway modulates EGFR stability in the EGFR-dependent phenotype. Further biochemical analyses demonstrated that the RAS/MAPK pathway mediates proliferation and survival of EGFR-dependent NSCLC cells. Finally, combinatorial treatment of EGFR-dependent NSCLC cell lines with small molecules targeting EGFR and the RAS/MAPK pathway yielded cytotoxic synergy. Thus, we have used pharmacogenomics methods to potentially improve NSCLC treatment by developing a method of predicting response and identifying an additional target to combine with EGFR TKIs to maximize responses

Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments

Conventional lung cancer treatments were once limited to surgery, radiation, and chemotherapy. However, gefitinib, a targeted drug, was launched in 2004, and the situation changed. Cancer cases that were highly responsive to gefitinib were later discovered to have epithelial growth factor receptor (EGFR) mutations. This discovery opened the door for biomarker-based treatment strategies. Subsequently, several EGFR-tyrosine kinase inhibitors (TKI) were developed, and they became a new mainstay of treatment for non-small cell lung cancer. In recent years, many mechanisms of resistance to EGFR-TKI have been elucidated; a mutation in the T790M gene at exon 20 is found in half of the resistant cases. Hence, osimertinib, which specifically inhibits EGFR despite this T790M gene mutation, was developed to achieve long-term progression-free survival. Other driver mutations that are similar to the EGFR mutation were discovered, including the EML4-ALK fusion gene (discovered in 2007), ROS1 gene, and BRAF gene mutations. The TKIs for each of these fusion genes were developed and are used as therapeutic agents. Another advancement in advanced non-small cell lung cancer is the development of immune checkpoint inhibitors. Four PD-1/PD-L1 inhibitors, including nivolumab, are currently available for treatment of lung cancer. These drugs prevent an escape from the cancer immunity cycle. This ensures that cancer cells will express cancer antigens, causing an anticancer immune response. Due to cancer immunotherapy, long-term survival is possible. The biomarker development for cancer immunotherapy and its side effects are actively being studied

Role of MicroRNA in Cancer Development and Treatment

Many researchers around the world have demonstrated that the expression of miRNAs is dysregulated in different tumors. Such dysregulation is caused by multiple mechanisms, and exposure to different carcinogens causes dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. Cancer cells with abnormal miRNA expression evolve the capability to sustain proliferative signaling, evade growth suppressors, resist cell death, activate invasion and metastasis, and induce angiogenesis. Genome-wide profiling demonstrates that miRNA expression signatures are associated with tumor type, tumor grade and clinical outcomes, so miRNAs could be potential candidates for diagnostic biomarkers, prognostic biomarkers, therapeutic targets and preventive screening programs. Although miRNAs have multiple targets, their function in tumorigenesis is due to their regulation of a few specific targets. After the first detection of altered miRNA in leukemia, microRNAs have been demonstrated to be constantly altered in all cancer. More recently, microRNA has been shown to be altered by exposure to environmental carcinogens, thus driving the whole process of carcinogenesis. Our aim is to provide a rigorous peer review and publish cutting-edge research on the role of microRNA in cancer prevention therapy to educate and inspire the scientific community worldwide

Proteomics

Biomedical research has entered a new era of characterizing a disease or a protein on a global scale. In the post-genomic era, Proteomics now plays an increasingly important role in dissecting molecular functions of proteins and discovering biomarkers in human diseases. Mass spectrometry, two-dimensional gel electrophoresis, and high-density antibody and protein arrays are some of the most commonly used methods in the Proteomics field. This book covers four important and diverse areas of current proteomic research: Proteomic Discovery of Disease Biomarkers, Proteomic Analysis of Protein Functions, Proteomic Approaches to Dissecting Disease Processes, and Organelles and Secretome Proteomics. We believe that clinicians, students and laboratory researchers who are interested in Proteomics and its applications in the biomedical field will find this book useful and enlightening. The use of proteomic methods in studying proteins in various human diseases has become an essential part of biomedical research

Tumor Suppressor Genes

Functional evidence obtained from somatic cell fusion studies indicated that a group of genes from normal cells might replace or correct a defective function of cancer cells. Tumorigenesis that could be initiated by two mutations was established by the analysis of hereditary retinoblastoma, which led to the eventual cloning of RB1 gene. The two-hit hypothesis helped isolate many tumor suppressor genes (TSG) since then. More recently, the roles of haploinsufficiency, epigenetic control, and gene dosage effects in some TSGs, such as P53, P16 and PTEN, have been studied extensively. It is now widely recognized that deregulation of growth control is one of the major hallmarks of cancer biological capabilities, and TSGs play critical roles in many cellular activities through signaling transduction networks. This book is an excellent review of current understanding of TSGs, and indicates that the accumulated TSG knowledge has opened a new frontier for cancer therapies