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Targeting Oncoproteins for Molecular Cancer Therapy

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… As for gefitinib, HPLC-MS identified desmethyl-gefitinib as a metabolite of gefitinib that is inactive in vitro and in vivo [ 43 ]. … Fig. 38.4 Molecular structure of gefitinib and bound to EGFR. ( a ) Molecular structure of gefitinib. ( b ) Crystal structure of gefitinib bound to EGFR kinase domain. …

Combination of Novel Therapies and New Attempts in Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, and it is rapidly falling without any effective therapeutic options. Although radical surgery, radiotherapy, and chemotherapy are performed on patients, the curative effect is suboptimal, and the survival rate is still poor. The discovery of altered gene pathways involved in this aggressive disease has advanced, but molecular targeted drugs targeting these pathways are still in clinical trials. To date, there is no effective way to treat this disease, so it is particularly urgent to find new treatments. At present, m

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… of ATCs overexpressing EGFR showed that gefitinib had a significant antitumor activity in this tumor. … Studies have also shown that gefitinib can enhance the toxicity of doxorubicin to ATC cells. A phase II trial was conducted to evaluate the efficacy of gefitinib (250 mg/day) in patients with advanced thyroid cancer. Of the 27 patients with ATC, 5 were enrolled. …

The Role of Plant-Derived Natural Products as a Regulator of the Tyrosine Kinase Pathway in the Management of Lung Cancer.

One of the most common malignant tumors worldwide is lung cancer, and it is associated with the highest death rate among all cancers. Traditional treatment options for lung cancer include radiation, chemotherapy, targeted therapy, and surgical resection. However, the survival rate is low, and the outlook is still dreadfully dire. The pursuit of a paradigm change in treatment approaches is, therefore, imperative. Tyrosine kinases (TKs), a subclass of protein kinases, regulate vital cellular function by phosphorylating tyrosine residues in proteins. Mutations, overexpression, and autocrine parac

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… In order to overcome gefitinib resistance, resveratrol increases intracellular gefitinib concentration, inhibits the removal of gefitinib from cells, and reduces CYP1A1 and ABCG2 expression. … When gefitinib accumulates in gefitinib-resistant NSCLC cells, it causes apoptosis, autophagy, and senescence [ 216 ]. The anti-NSCLC actions of gefitinib are consequently enhanced when co-treated with resveratrol. …

Cutaneous adverse events to systemic antineoplastic therapies: a retrospective study in a public oncologic hospital.

BackgroundMucocutaneous adverse events are common during anticancer treatment, with variable consequences for the patient and their therapeutic regimen.ObjectiveTo evaluate the most common adverse events, as well as the drugs associated with their appearance and the consequences for cancer treatment.MethodsA retrospective study was carried out through the analysis of patients treated at the Clinical Dermatology Unit of a public oncologic hospital.ResultsA total of 138 patients with 200 adverse events were evaluated. The most commonly identified adverse events were nail and periungual changes (

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… 10/2) | Paclitaxel (2), Daunorubicin (1), Doxorubicin and cyclophosphamide (1) Periungual pyogenic granuloma | 3 (7.5/1.5) | Panitumumab (2), Erlotinib (1) Onychodystrophy | 2 (5/1) | Docetaxel (1), Gefitinib (1) Onychomadesis | 1 (2.5/0.5) | Paclitaxel (1) Onychocryptosis | 1 (2.5/0.5) | Gefitinib ( … As for xerosis, it affected 12 patients (6.0%) and was mostly caused by EGFR inhibitors (panitumumab, erlotinib and gefitinib). …

Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.

Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistan

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… resistance | Interim data: 98 pts with FISH MET amp: ORR: 43.9% mDOR: 9.7 m mPFS: 5.4 m 31 pts with NGS MET amp: ORR: 51.6% mDOR: 5.6 m mPFS: 4.6 m | Ib/II | NCT01982955 (INSIGHT) | Gefitinib | MET inhibitor | Gefitinib+tepotinib vs. … CT | MET overexpression (IHC2+ or 3+) or MET NSCLC progressed on EGFR‐TKI | In EGFR T790M−: ORR: 67 vs. 43% mDOR: 19.9 vs. 2.8 m mPFS: 16.6 vs. 4.2 m mOS: 37.3 vs. 13.1 m | 250 Ib/II | NCT01610336 | Gefitinib | MET inhibitor | Gefitinib+capmatinib | EGFR ‐mutated, MET ‐amplified/overexpressing NSCLC …

Molecular targets for anticancer therapies in companion animals and humans: what can we learn from each other?

Despite clinical successes in the treatment of some early stage cancers, it is undeniable that novel and innovative approaches are needed to aid in the fight against cancer. Targeted therapies offer the desirable feature of tumor specificity while sparing healthy tissues, thereby minimizing side effects. However, the success rate of translation of these therapies from the preclinical setting to the clinic is dramatically low, highlighting an important point of necessary improvement in the drug development process in the oncology field. The practice of a comparative oncology approach can addres

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… In vitro studies with a feline OSCC cell line have been conducted to target EGFR with the TKI gefitinib and RNA interference 44 , 45 . While gefitinib caused a reduction in cell proliferation, this was accomplished at a relatively high dose and gefitinib resistance developed. … Cetuximab and its caninized version (can225IgG), gefitinib and EGFR siRNA have all inhibited cell proliferation as a single agent 61 - 63 . Only in one of these studies a FMC cell line was included, also showing cell proliferation inhibition after gefitinib treatment 62 . …

Vitamin d: pharmacokinetics and safety when used in conjunction with the pharmaceutical drugs used in cancer patients: a systematic review.

Vitamin D has reported anti-cancer and anti-inflammatory properties modulated through gene transcription and non-genomic signaling cascades. The purpose of this review was to summarize the available research on interactions and pharmacokinetics between vitamin D and the pharmaceutical drugs used in patients with cancer. Hypercalcemia was the most frequently reported side effect that occurred in high dose calcitriol. The half-life of 25(OH)D3 and/or 1,25(OH)2D3 was found to be impacted by cimetidine; rosuvastatin; prednisone and possibly some chemotherapy drugs. No unusual adverse effects in ca

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… with Gefitinib. … Week 2: 250 mg Gefitinib daily Week3: 4 mg dexamethasone, iv calcitriol with 250 mg Gefitinib daily. …

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies.

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morb

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… These reported SCAR cases were associated with 17 targeted anticancer agents and immunotherapies, including EGFR inhibitors (afatinib, cetuximab, erlotinib, gefitinib, panitumumab, and vandetanib), multikinase inhibitors (imatinib), antiangiogenic agents (sorafenib), proteasome (bortezomib), anti-CD20 … EGFR inhibitors (n=12) were the most common group of drugs to induce SJS/TEN, including cetuximab (n=4), afatinib (n=2), gefitinib (n=2), vandetanib (n=2), erlotinib (n=1), and panitumumab (n=1). Imatinib was also the most common offending drug to induce DERSS and AGEP. …

Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review.

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells' sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene rever

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… In another study, a combination of elemene and gefitinib (GEF) produced better results compared to single drug treatment in cells with multiple 150-fold resistance to gefitinib. … A combination of c-Met inhibitor SU11274 with gefitinib on HGF-induced PC-9 cells significantly decreased the survival rate compared to that of gefitinib alone on HGF-induced PC-9 cells. …

Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer.

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhan

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… In a gefitinib-resistant lung cancer cell line (H1975), a combination of 15 µM of curcumin and 1 µM of gefitinib was found to have the same antiproliferative effect as 20 µM of gefitinib ( Lee et al., 2011 ). … Several other curcumin and gefitinib combination studies also found that curcumin promotes the inhibitory activity of gefitinib through downregulation of EGFR, MAPK, and PI3K signaling pathways ( Lee et al., 2007 ; Xin et al., 2017 ; Chen et al., 2019 ). …

Clinical development of targeted and immune based anti-cancer therapies.

Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to

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… Gefitinib was the first commercially available inhibitor of the EGFR tyrosine kinase domain. … Year | Sponsor | Phase | N | Median OS (months) | Median PFS (months) Small-molecule EGFR TKIs 1st Generation EGFR TKI Gefitinib (Iressa®/ZD1839) Gefitinib (250 mg/d) | NCT00322452 | IPASS | NSCLC | Chemotherapy | 2006–2010 | AstraZeneca | III | 1329 | 18.6 vs 17.3 | 5.7 vs 5.8/24.9 vs 6.7% Gefitinib …

Association of tumor mutation burden and epidermal growth factor receptor inhibitor history with survival in patients with metastatic stage III/IV non-small-cell lung cancer: A retrospective study.

ObjectivesLung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only.MethodsA total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death.

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… Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8. doi: 10.1056/NEJMoa0909530. 7. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. … Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 2007;13(17):5150–5. doi: 10.1158/1078-0432.CCR-07-0560. 21. …

Targeted therapy in the treatment of malignant gliomas.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In additi

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… Sirolimus has been evaluated in combination with the EGFR TKIs erlotinib or gefitinib in a retrospective case series of patients with recurrent malignant gliomas. … Rich JN Reardon DA Peery T Phase II trial of gefitinib in recurrent glioblastoma J Clin Oncol 2004 22 1 133 142 14638850 10.1200/JCO.2004.08.110 126. …

Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV), a type 4 γ herpes virus, is recognized as a causative agent in nasopharyngeal carcinoma (NPC). Incidence of EBV-positive NPC have grown in recent decades along with worse outcomes compared with their EBV-negative counterparts. Latent membrane protein 1 (LMP1), encoded by EBV, induces NPC progression. The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases (RTK), is a driver of tumorigenesis, including for NPC. Little data exist on the relationship between EGFR and EBV-induced NPC. In our initial review, we found that LMP1

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… In addition to inhibiting the kinase, Gefitinib also increases the formation of the inactive EGFR dimer, suggesting that Gefitinib could induce faster endocytosis and dimer degradation. … Phase II study of gefitinib for the treatment of recurrent and met-astatic nasopharyngeal carcinoma. Head Neck. 2008;30:863–867. doi: 10.1002/hed.20792. …

Arrhythmias, conduction disorders and sudden cardiac death in cancer patients and survivors: expert opinion of the working groups on cardio-oncology and on electrophysiology of the hellenic cardiac society.

Advances in cancer therapeutics have significantly improved patient survival; however, cardiotoxic effects-including arrhythmias-have emerged as a growing clinical concern. This expert opinion, developed by the Working Groups on Cardio-Oncology and Electrophysiology of the Hellenic Cardiological Society, aims to raise awareness of the increasing burden of arrhythmias in cancer patients and survivors. This document explores the multifactorial etiology of arrhythmias in this population, including patient-related factors, the direct effects of malignancy, and the arrhythmogenic potential of thera

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… ) SERM (tamoxifen) | Common metabolism in CYP2D6 | Alternative antiarrhythmic agent or regular monitoring for signs of toxicity such as QTc prolongation, PR or QRS widening Propafenone | Angiogenesis inhibitor (pomalidomide) Anthracycline (doxorubicin) EGFR TKI (erlotinib, gefitinib) SERM (tamoxifen) … EGFR/VEGF TKI (vandetanib, axitinib, pazopanib, regorafenib, sorafenib, sunitinib, erlotinib, gefitinib, lapatinib, neratinib, osimertinib) FLT3 inhibitor (gilteritinib) HDAC inhibitor (panobinostat) Hedgehog pathway inhibitor (glasdegib, sonidegib) IDH1 inhibitor (ivosidenib) MEK inhibitor (cobimetinib …

Kinase Inhibitors and Ovarian Cancer.

Ovarian cancer is fifth in the rankings of cancer deaths among women, and accounts for more deaths than any other gynecological malignancy. Despite some improvement in overall-(OS) and progression-free survival (PFS) following surgery and first-line chemotherapy, there is a need for development of novel and more effective therapeutic strategies. In this mini review, we provide a summary of the current landscape of the clinical use of tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors in ovarian cancer. Emerging data from phase I and II trials reveals that a

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… Gefitinib : Gefitinib is an oral aniline quinoline compound which functions through inhibition of EGFR. It has been approved by the FDA for the treatment of non-small cell lung cancer. In vitro, gefitinib has shown to inhibit growth in human ovarian cancer cell lines [ 44 ]. … In a study on an HPV induced ovarian squamous cell carcinoma where the patient developed bone metastases, the patient did not respond to gefitinib [ 45 ]. …

CELL BIOLOGY AND SIGNALING

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Althou … on under EGF or PDGF ligand stimulation in vitro. Simultaneous inhibition of both EGFR and PDGFR by gefitinib and imatinib was necessary to suppress PI3 kinase pathway activation. Analysis of whole exome and whole genome sequencing of coamplified TCGA samples and cell line subpopulations supports a common clonal origin with late divergence of RTK-amplified …

Gene editing in cancer therapy: overcoming drug resistance and enhancing precision medicine.

The CRISPR system has revolutionized cancer gene therapy, offering unparalleled precision in genetic manipulation for targeted oncogene disruption, mutation correction, and immune system modulation. This breakthrough tool has demonstrated remarkable potential in overcoming drug resistance, enhancing chemotherapy sensitivity, and improving immunotherapy strategies such as CRISPR-engineered CAR-T cells. Additionally, oncolytic virus-mediated CRISPR delivery has emerged as a novel approach for tumor-specific gene editing, minimizing off-target effects. The rapid transition of CRISPR-based cancer

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… This dual base editing approach achieved editing frequencies of 6.1% in TP53 and 27.1% in EGFR in a xenograft mouse model of NSCLC, enhancing sensitivity to gefitinib and leading to successful tumor regression. … Indeed, A-to-I edited miR-411–5p directly suppressed MET and the ERK/MAPK pathway, leading to enhanced sensitivity to gefitinib and osimertinib in TKI-resistant NSCLC cell lines. …

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat.

The Food and Drug Administration (FDA) has approved vorinostat, also called Zolinza®, for its effectiveness in fighting cancer. This drug is a suberoyl-anilide hydroxamic acid belonging to the class of histone deacetylase inhibitors (HDACis). Its HDAC inhibitory potential allows it to accumulate acetylated histones. This, in turn, can restore normal gene expression in cancer cells and activate multiple signaling pathways. Experiments have proven that vorinostat induces histone acetylation and cytotoxicity in many cancer cell lines, increases the level of p21 cell cycle proteins, and enhances p

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… PC9 (PC9GR) cells | Hoechst 33258 staining | Vorinostat + Gefitinib induced cell death in parental PC9 cells by activating apoptosis to a greater extent than Gefitinib alone | [ 75 ] Assessment of reactive oxygen species (ROS) production | Vorinostat + Gefitinib, in both PC9 and PC9GR cells, resulted … In PC9 gefitinib-resistant (PC9GR) cancer cells and parental PC9 cells, this combination promoted cell death via apoptosis activation more effectively than gefitinib alone and induced Hsp90 cleavage with reduced levels of its clients (AKT, MET, and EGFR). …

Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors.

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKIs), significant impact has been made in cancer chemotherapeutics. However, some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient variations in plasma concentration-time profiles. Thus, therapeutic drug monitoring, dose adjustments and precision medicine are being contemplated by clinicians. Complex formulations or nanoformulation-based drug d

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… A case study on NP delivery of gefitinib (GFT), an EGFR inhibitor used in non-small cell lung cancer (NSCLC), demonstrated that NPs could enhance drug delivery to tumor cells while reducing systemic toxicity. … l T 1/2 : 36.0 h PPB: 93% Futibatinib LYTGOBI® | Metastatic intrahepatic cholangiocarcinoma with FGFR2 gene fusion; 2022 | Tablet;20 mg q.d.; Inhibits FGFR2 | IC 50 : 0.7 nM AUC 24 h : 790 ng·h/ml C max : 144 ng/ml Vd (steady state): 66 l T max : 2 h; T 1/2 : 2.9 h PPB: 95% Cl (steady state):20 l/h Gefitinib …