Overview of pathophysiology and drug targets for non-small-cell lung cancer

2012 ◽  
pp. 6-16
Author(s):  
Anish Thomas ◽  
Arun Rajan ◽  
Giuseppe Giaccone
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 620 ◽  
Author(s):  
Connor O’Leary ◽  
Wen Xu ◽  
Nick Pavlakis ◽  
Derek Richard ◽  
Ken O’Byrne
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Response Rates ◽  
Small Cell ◽  
Small Cell Lung ◽  
Asian Ethnicity

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

scholarly journals The SOX9-Aldehyde Dehydrogenase Axis Determines Resistance to Chemotherapy in Non-Small-Cell Lung Cancer

2019 ◽  
Vol 40 (2) ◽  
Author(s):  
Maria A. Voronkova ◽  
Liying W. Rojanasakul ◽  
Chayanin Kiratipaiboon ◽  
Yon Rojanasakul
Keyword(s):  
Lung Cancer ◽  
Transcription Factor ◽  
Small Cell Lung Cancer ◽  
Aldehyde Dehydrogenase ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Tumor Initiating Cells

ABSTRACT Chemotherapy resistance and tumor relapse are the major contributors to low patient survival, and both have been largely attributed to cancer stem-like cells (CSCs) or tumor-initiating cells (TICs). Moreover, most conventional therapies are not effective against CSCs, which necessitates the discovery of CSC-specific biomarkers and drug targets. Here, we demonstrated that the embryonic transcription factor SOX9 is an important regulator of acquired chemoresistance in non-small-cell lung cancer (NSCLC). Our results show that SOX9 expression is elevated in NSCLC cells after treatment with the chemotherapeutic cisplatin and that overexpression of SOX9 correlates with worse overall survival in lung cancer patients. We further demonstrated that SOX9 knockdown increases cellular sensitivity to cisplatin, whereas its overexpression promotes drug resistance. Moreover, this transcription factor promotes the stem-like properties of NSCLC cells and increases their aldehyde dehydrogenase (ALDH) activity, which was identified to be the key mechanism of SOX9-induced chemoresistance. Finally, we showed that ALDH1A1 is a direct transcriptional target of SOX9, based on chromatin immunoprecipitation and luciferase reporter assays. Taken together, our novel findings on the role of the SOX9-ALDH axis support the use of this CSC regulator as a prognostic marker of cancer chemoresistance and as a potential drug target for CSC therapy.

Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets

2015 ◽  
Vol 52 (2) ◽  
pp. 243 ◽  
Author(s):  
VidyaH Veldore ◽  
S Patil ◽  
CT Satheesh ◽  
HP Shashidhara ◽  
R Tejaswi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Molecular Subtype ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
New Drug

scholarly journals Current Drugs and Drug Targets in Non-Small Cell Lung Cancer: Limitations and Opportunities

2015 ◽  
Vol 16 (10) ◽  
pp. 4147-4156 ◽  
Author(s):  
Aditi Daga ◽  
Afzal Ansari ◽  
Shanaya Patel ◽  
Sheefa Mirza ◽  
Rakesh Rawal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Identification of Biomarker Signatures and Candidate Drugs in Non-Small Cell Lung Cancer

2019 ◽  
Author(s):  
Amina Rownaq ◽  
Md. Parvez Mosharaf ◽  
S. M. Shahinul Islam ◽  
Md. Nurul Haque Mollah
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Expression Profiles ◽  
Experimental Studies ◽  
Small Cell ◽  
Potential Drug ◽  
Small Cell Lung ◽  
Potential Drug Targets

Lung cancer is one of the most important health risks worldwide for human. Non-small cell lung cancer (NSCLC) is the most common cause of premature death from malignant disease. This study provides in-depth insights from systems biology analyses to identify molecular to inform systemic drug targeting in NSCLC. Gene expression profiles from non small cell lung cancer were analyzed with genome-scale biomolecular networks (I,e., protein-protein interaction, transcriptional and post transcriptional regulatory networks). The aim of the study was to determine the pathways and expression profile of the genes to discover molecular signature at RNA and protein levels which could serve as potential drug targets for therapeutics innovation and the identification of novel targets. Eight proteins, six TFs and seven miRNAs came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq. Risk discrimination performance of the reporter biomolecules NPR3, JUN, PPARG, TP53, CKMT1A, SP3 and TFAP2A were also evaluated. Total 213 drugs and 7 proteins were found for non small cell lung cancer through dgidb. Among these identified drugs seven drugs such as- Gemcitabine, Carboplatin, paclitaxel, Docetaxel, Crizotinib, Bevacizumab and Gemcitabine is used for NSCLC which is approved by National Cancer Institute. The molecular signatures and repurposed drugs presented here permit further attention for experimental studies which are offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of NSCLC.

scholarly journals Genotyping and Genomic Profiling of Non–Small-Cell Lung Cancer: Implications for Current and Future Therapies

2013 ◽  
Vol 31 (8) ◽  
pp. 1039-1049 ◽  
Author(s):  
Tianhong Li ◽  
Hsing-Jien Kung ◽  
Philip C. Mack ◽  
David R. Gandara
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Novel Drug ◽  
Novel Drug Targets

Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non–small-cell lung cancer (NSCLC). Over the last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patient's clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patient's tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.

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