Current Status and Perspectives Regarding the Therapeutic Potential of Targeting EGFR Pathway by Curcumin in Lung Cancer
Mojtaba ShafieeElham MohamadzadeSoudabeh ShahidsalesSamaneh KhakpouriMina MaftouhSeyed Alireza ParizadehSeyed Mahdi HasanianAmir Avan
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Lung cancer is among the leading causes of cancer-related-death. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. More than 70% of NSCLC patients have locally advanced or metastatic disease in diagnosis stage, which are then being treated with platinum-based chemotherapy or epidermal-growthfactor- receptor (EGFR) inhibitors. Several molecules which target multiple ErbB receptors and EGFR have been developed, including gefitinib and erlotinib. Identification of novel agents with less toxicity is warranted. Several interesting data have been reported about the antitumor activity of curcumin in several tumors, including lung, breast and colorectal cancers. In particular, a recent phase I trial evaluated the activity of curcumin in combination with FOLFOX chemotherapy in patients with inoperable colorectal cancer. They showed that curcumin added benefit in subsets of patients when administered with FOLFOX and was well-tolerated chemotherapy adjunct. Another ongoing trial is now investigating the beneficial effects of curcumin plus gefitinib or erlotinib for EGFRmutant NSCLC. Improved understanding of molecular mechanisms behind resistance to EGFR tyrosine kinase inhibitors suggests the importance of a genotype-guided approach to therapy and inhibition of parallel and downstream pathways, using agents which target heat-shock-protein-90, poly (ADP-ribose) polymerase and PI3K/mTOR pathway. The aim of the current review is to give an overview of the possible molecular mechanisms of curcumin in the preclinical and clinical investigations in solid tumors, with particular emphasis on its combination with other chemotherapeutic agents in lung cancers.Osimertinib
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Optimization strategies of first-line treatment of patients with advanced non-small cell lung cancer
Lung cancer is a leading cause of cancer-related death worldwide.It is possible to achieve marginal improvement in overall survival of patients with advanced non-small-cell lung cancer(NSCLC) by optimizing strategies of drugs treatment.The platinum-based doublet chemotherapy has been considered as the standard first-line treatment for NSCLC with the highest treatment efficacy.Erlotinib and gefitinib appear to be especially effective for tumors with gene mutations of activated epidermal growth factor receptor.Further investigations with valid comparison groups are necessary in order to better define their optimal treatment modality.
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Treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring activating mutations in the epidermal growth factor receptor (EGFR) with EGFR-directed tyrosine kinase inhibitors (TKI) has become a paradigm for the therapeutic potential of personalized cancer treatment. Never before treatment results were reported for a defined NSCLC subgroup comparable with the outcome reported in clinical trials evaluating treatment of EGFR-mutated NSCLC with either gefitinib or erlotinib. For instance, in a recent trial of the Spanish Lung Cancer Group 217 patients with EGFR mutated advanced NSCLC were treated with erlotinib either first - or second line with a remission rate of 71%, a median time to progression (TTP) of 14 months and a median overall survival time (OS) of 27 months (1).
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Lung cancer is the foremost cause of cancer-related deaths world-wide. Both, the major forms of lung cancer, Non-small cell lung cancer (NSCLC) and Small cell lung cancers (SCLC), have responded effectively to chemo-, radiation and adjuvant-therapies. Tumor removal through surgery also appeared as a good therapeutic strategy. However, these therapies demonstrated unfavourable side-effects, and hence novel drugs targeting lung cancer emerged essential. Activation of epidermal growth factor receptor (EGFR)-tyrosine kinases is a key reason for lung cancer progression. Two important strategies that have attenuated lung cancers were through treatments with EGFR-tyrosine kinase-inhibitors, erlotinib and gefitinib, or EGFR-neutralizing antibodies, cetuximab and bevacizumab. A major advantage with erlotinib and gefitinib was their role in second and third-line treatments following chemotherapies. Phase II/III clinical trials showed that combinatorial treatment of tyrosine kinase (TK)-inhibitors with chemotherapeutics, such as docetaxel and pemetrexed, caused significant improvements in progression-free survival and overall survival.Phase I and II clinical studies also revealed that combination of tyrosine kinase-inhibitors with the EGFR-targeted antibodies was an effective approach for treating lung cancer. However, patients having T790M-mutations within EGFR gene were resistant to erlotinib and gefitinib. Alternatively, another second-generation EGFR-tyrosine kinase-inhibitor, afatinib, that could circumvent the problem of drug resistance has been developed as lung cancer therapy. The current review focuses on the role of EGFR in lung cancer progression and apprises about the EGFR-targeted therapies. The review also informs on the adverse side-effects of these therapies and enlightens the need for safer therapeutic regimens to eradicate this dreaded disease.
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The development of tyrosine kinase inhibitors gefitinib and erlotinib for anti-epidermal growth factor receptor (EGFR) therapy is one of milestones in the history for treatment of lung cancer, a disease that annually causes more than 158,000 deaths in the United States, 610,000 deaths in China, and 1.6 million deaths worldwide (1,2). Activating mutations in the tyrosine kinase domain of the EGFR gene are known to be an oncogenic driver in lung tumorigenesis. It is now clear that non-small cell lung cancer (NSCLC) with EGFR activating mutations represent a distinct biological subtype that is highly sensitive to the treatment with EGFR inhibitors. In fact, the finding that EGFR-mutant lung cancer cells are highly susceptible to the EGFR inhibitors gefitinib (3) and erlotinib (4) has made these two agents the first choice for therapy in patients whose tumors harbor EGFR mutations. Both gefitinib and erlotinib have been reported to significantly improve disease control, objective response rate (ORR), progression-free survival (PFS), and quality of life in patients with EGFR-mutant lung cancer, when compared with conventional chemotherapy (5,6). Approximately 10−17% of lung adenocarcinomas patients in the United States and Europe (7,8) and about 30−65% of lung cancer patients in Asia have EGFR activating mutations (9,10). Deletions in exon 19 and the point mutation L858R in exon 21 are the most common EGFR activating mutations, accounting for about 85% of the EGFR mutations detected in lung cancers (10,11). In the absence of EGFR mutation or gene amplification, there is no significant difference in the responses to the treatment with EGFR inhibitors and conventional chemotherapies (12). Thus, EGFR gene mutation test is mandatory for using EGFR antagonists as the first-line treatment for advanced NSCLC (13). Consequently, genetic profiling of surgical and biopsy samples is routinely performed clinically for lung cancer patients to provide guidance for selection of treatment regimens. A number of DNA sequencing and polymerase chain reaction (PCR) based methods are used clinically to detect EGFR gene mutations in tumor specimens. However, the presence of intratumoral heterogeneity in most cancer patients (14) has imposed a challenge in using the information obtained from analysis of single tiny biopsy samples in clinical practice. Moreover, multiple and serial biopsies are often impractical clinically because of the potential complications of the procedures, including tumor seeding or spreading following percutaneous needle biopsy (15,16).
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Lung cancer is the leading cause of cancer-related death in the world as well as in China. It is estimated that approximately 429 000 Chinese individuals may die from lung cancer in 2005, and the mortality rate for lung cancer will double in the next century.1 Currently, chemotherapy is the a main treatment of advanced and recurrent lung cancer. However, the recent development of tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib may change the therapeutic approaches for this disease.
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Better methods of combating non-small-cell lung cancer (NSCLC) are constantly being sought. The recent movement towards the implementation of a personalised approach to treatment in oncology is a positive step in this direction. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs such as gefitinib (Iressa®) and erlotinib (Tarceva®) are approved for the treatment of certain types and stages of non-small-cell lung cancer (NSCLC). It is now possible to determine the likelihood of response of a given patient’s tumour to treatment with this type of cancer drug using molecular diagnostic methods that detect the presence or absence of specific EGFR mutations. These diagnostic and therapeutic advances offer the potential to improve patient care and bring new hope to cancer patients.
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// Xiaofei Wang 1, 2,* , Keqiang Chen 2, *, Ying Yu 2, 3, Yi Xiang 1, Jae Hong Kim 2, Wanghua Gong 4, Jiaqiang Huang 5, Guochao Shi 1, Qingyun Li 1, Min Zhou 1, Thomas Sayers 4, Poonam Tewary 4, Beili Gao 1 and Ji Ming Wang 2 1 Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China 2 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA 3 Eye Institute, Affiliated Hospital of Nantong University, Nantong 226001, China 4 Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA 5 College of Life Sciences and Bioengineering, School of Sciences, Beijing Jiaoton University, Beijing 100044, China * These authors have contributed equally to this work Correspondence to: Ji Ming Wang, email: wangji@mail.nih.gov Beili Gao, email: yshu7661@sina.com Keywords: lung cancer; metformin; EGFR; erlotinib; phosphorylation Received: July 14, 2017 Accepted: August 21, 2017 Published: November 21, 2017 ABSTRACT Lung cancer is one of the deadliest malignant tumors with limited treatment options. Although targeted therapy, using tyrosine-kinase inhibitors such as erlotinib (Erlo), has shown therapeutic benefit, only 15 % patients with mutated epidermal growth factor receptor (EGFR) in lung cancer cells are sensitive. Therefore, additional therapeutic strategy should be developed. In this study, we found that metformin (Met), which is widely used for the treatment of type 2 diabetes (T2D), sensitized lung cancer cells bearing wild-type EGFR to Erlo treatment by enriching cancer cells expressing higher levels of EGFR with persistent phosphorylation. As a consequence, combination of Met and Erlo more efficiently inhibited the growth of lung cancer cells both in vitro and in mice with xenografted tumors. Our results suggest a novel approach to treating lung cancer cases which are originally resistant to Erlo.
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Better methods of combating non-small-cell lung cancer (NSCLC) are constantly being sought. The recent movement towards the implementation of a personalized approach to treatment in oncology is a positive step in this direction. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs such as gefitinib (Iressa®) and erlotinib (Tarceva®) are approved for the treatment of certain types and stages of non-small-cell lung cancer (NSCLC). It is now possible to determine the likelihood of response of a given patient’s tumor to treatment with this type of cancer drug using molecular diagnostic methods that detect the presence or absence of specific EGFR mutations. These diagnostic and therapeutic advances offer the potential to improve patient care and bring new hope to cancer patients.
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