scholarly journals Varlitinib induced differential Protein Expression analysis on oral carcinoma cell line: A therapeutic approach

2021 ◽  
Author(s):  
Fariha Tanveer ◽  
Amber Ilyas ◽  
Basir Syed ◽  
Zehra Hashim ◽  
Aftab Ahmed ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Differential Expression ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Oral Carcinoma ◽  
Type I ◽  
Quinazoline Derivative ◽  
Ligand Complex ◽  
Differential Expression Pattern

Abstract Receptor-ligand complex mediated signaling significantly contributesin cellular activities such as growth, proliferation, differentiation, and survival. However, augmented expression of signal transducing receptors and ligands is the most frequent molecular event and major hallmark of oral carcinogenesis. Among these receptors, Epidermal Growth Factor Receptor (EGFR) with intracellular tyrosine kinase activity is the most frequently overexpressed molecule by Squamous epithelial cells of oral cavity. Aberrated EGFR mediated signaling has laid the foundation of targeted therapy thus providing rationale for the conducted study. We have selected EGFR pathway as targeted intracellular signaling cascade inOral squamous cell carcinoma (OSCC). Deactivating EGFR by blocking the binding sites is likely to result in prevention of intracellular downstream signaling. In this context, Tyrosine Kinase Inhibitors (TKIs) have come into play. Quinazolines (aromatic heterocyclic compounds) and their derivatives have shown promising clinical outcomes. Present study focused to investigate anti-EGFR potential of quinazoline derivative, varlitinib-a pan-EGFR inhibitor on oral squamous epithelial cell lines. We performed proteomic analyses to identify differential expression pattern of proteins in SCC-25 cells in response to varlitinib treatment. Identified proteins include Binding Immunoglobulin Protein (BiP), Heat Shock Protein 7C (HSP7C), Protein Disulfide Isomerase 1 A (PDIA1), Vimentin (VIME), Keratin type I Cytoskeletal 14 (K1C14), and β-Actin (ACTB). Among these, five proteinswere found to be downregulated upon varlitinib treatment whereas only Keratin type I Cytoskeletal 14 was upregulated. Differential expression of proteins and possible role of varlitinib as potential antitumor drug in oral carcinoma is discussed.

Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity

2019 ◽  
Vol 4 (38) ◽  
pp. eaav6473 ◽  
Author(s):  
Zhida Liu ◽  
Chuanhui Han ◽  
Chunbo Dong ◽  
Aijun Shen ◽  
Eric Hsu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Type I ◽  
First Line ◽  
Tumor Relapse ◽  
Egfr Tyrosine Kinase ◽  
Tki Treatment ◽  
Egfr Tki

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non–small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand–1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

scholarly journals Clinical and Molecular Features of Epidermal Growth Factor Receptor (EGFR) Mutation Positive Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Tyrosine Kinase Inhibitors (TKIs): Predictive and Prognostic Role of Co-Mutations

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2425
Author(s):  
Paolo Bironzo ◽  
Maria Lucia Reale ◽  
Tessa Sperone ◽  
Fabrizio Tabbò ◽  
Andrea Caglio ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Nsclc Patients

Background: Tyrosine kinase inhibitors (TKIs) show variable efficacy in epidermal growth factor receptor mutation-positive (EGFR+) NSCLC patients, even in patients harbouring the same mutation. Co-alterations may predict different outcomes to TKIs. Methods: We retrospectively analysed all consecutive EGFR+ advanced NSCLC treated with first-line TKIs at our Institutions. NGS with a 22 genes clinical panel was performed on diagnostic specimens. PD-L1 expression was also evaluated. Results: Of the 106 analysed specimens, 59 showed concomitant pathogenic mutations. No differences in OS (mOS 22.8 vs. 29.5 months; p = 0.088), PFS (mPFS 10.9 vs. 11.2 months; p = 0.415) and ORR (55.9% vs. 68.1%; p = 0.202) were observed comparing patients without and with co-alterations. Subgroup analysis by EGFR mutation type and TKIs generation (1st/2nd vs. 3rd) did not show any difference too. No correlations of PD-L1 expression levels by co-mutational status were found. Significant associations with presence of co-alterations and younger age (p = 0.018) and baseline lymph nodes metastases (p = 0.032) were observed. Patients without concomitant alterations had a significant higher risk of bone progression (26.5% vs. 3.3%, p = 0.011). Conclusions: Pathogenic co-alterations does not seem to predict survival nor efficacy of EGFR TKIs in previously untreated advanced NSCLC.

Successful retreatment with erlotinib after erlotinib-related interstitial lung disease

2021 ◽  
pp. 030089162110200
Author(s):  
Haci M. Turk ◽  
Mustafa Adli ◽  
Melih Simsek ◽  
Altay Aliyev ◽  
Mehmet Besiroglu
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Lung Disease ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Background: Epidermal growth factor receptor tyrosine kinase inhibitors are effectively being used in the treatment of non-small cell lung cancer. Although most of their adverse effects are mild to moderate, they occasionally can cause life-threatening interstitial lung disease. We aimed to present a case of lung adenocarcinoma successfully re-treated with erlotinib after recovery with effective treatment of erlotinib-induced interstitial lung disease. Case description: A 54-year-old nonsmoking woman was diagnosed with metastatic adenocarcinoma of the lung. After progression with first-line chemotherapy, erlotinib 150 mg daily was initiated. On the 45th day of erlotinib treatment, interstitial lung disease occurred and erlotinib was discontinued. Clinical improvement was achieved with dexamethasone treatment and erlotinib was re-initiated. Ten weeks after re-initiation of erlotinib, 100 mg daily partial response was observed. Conclusions: Incidence of interstitial lung disease is higher in men, smokers, and patients with pulmonary fibrosis. Interstitial lung disease radiologically causes ground-glass opacity and consolidation. The physician should quickly evaluate new respiratory symptoms in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors, discontinue the epidermal growth factor receptor tyrosine kinase inhibitor treatment, and initiate corticosteroids if clinical diagnosis is interstitial lung disease.

Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer

2005 ◽  
Vol 23 (11) ◽  
pp. 2445-2459 ◽  
Author(s):  
José Baselga ◽  
Carlos L. Arteaga
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Gene ◽  
Epidermal Growth ◽  
Egfr Tkis ◽  
Receptor Family

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

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