osimertinib and Neoplasms

The polycomb repressive complex 2 (PRC2), which comprised of the core subunits: Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), and Embryonic Ectoderm Development (EED), is an essential epigenetic gene silencer responsible for depositing repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on chromatin. The aberrant activity of PRC2 is closely involved in tumorigenesis and progression, making its inhibition a viable strategy for epigenetic cancer therapy. Although the clinical development of small PRC2 inhibitors has made impressive progress, with one EZH2 inhibitor approved for cancer therapy and several other candidates in clinical trials, current EZH2 inhibitors are limited to treating certain hematological malignancies and have acquired drug resistance. EED is essential for PRC2 stabilization and allosterically stimulating PRC2 activity because it functions as a scaffold protein and an H3K27me3-recognizing protein. Thus, due to its novel mechanism of action, targeting EED provides a promising new strategy for inhibiting PRC2 function and exhibits the potential to overcome the issues encountered by EZH2 inhibitors. This review provides a comprehensive overview of available cancer therapy strategies that target EED, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and proteolysis-targeting chimeras (PROTACs).

Topics: Ectoderm; Enhancer of Zeste Homolog 2 Protein; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Polycomb Repressive Complex 2

Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.

Topics: Antineoplastic Agents; DNA Damage; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms; Protein Kinases; Proteins; Structure-Activity Relationship; Topoisomerase Inhibitors

Histone deacetylases (HDACs) are a class of enzymes that remove acetyl from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis. As a result, HDACs represent an excellent target for anti-cancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified in the last decade with numerous HDACis being discovered, and some of them have reached the market. However, currently available HDACis are mostly non-isoform selective and suffer from several drawbacks such as limited efficacy, drug resistance, and toxicities. Therefore, isoform-selective HDACis and HDACis with dual targeting capabilities have attracted much attention from academia to industry in the past 5 years, and great advances have been achieved in this area. In this paper, we summarize recent progress on HDACis with dual targeting capabilities and their potential application to cancer treatment.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Structure; Neoplasms

First generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib) demonstrate excellent clinical efficacy for NSCLC patients carrying EGFR oncogenic mutations (L858R, del exon 19 deletions between amino acids 746 and 750). Invariable, drug resistance occurs with around 60% of it driven by the EGFR-T790M gatekeeper mutation. To counter the T790M-dependent resistance, third generation covalent EGFR inhibitors have been developed with high potency toward T790M containing mutants and selectivity over WT EGFR. This review provides an overview of the third generation drugs currently in clinical trials and also encompasses novel methodologies developed to discover third generation covalent EGFR drugs.

Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Neoplasms; Protein Kinase Inhibitors

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on C

Topics: Acrylamides; Administration, Oral; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Area Under Curve; Female; Hepatic Insufficiency; Humans; Kidney Function Tests; Male; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Severity of Illness Index

Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (

Topics: Acrylamides; Aged; Aniline Compounds; Female; Humans; Liver; Male; Middle Aged; Neoplasms

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Mice, Nude; Mice, SCID; Mutation; Neoplasms; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrimidines; Rats; Xenograft Model Antitumor Assays

Topics: Acrylamides; Adolescent; Adult; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Female; Glucocorticoids; Humans; Immune Checkpoint Inhibitors; Ipilimumab; Male; Middle Aged; Neoplasms; Nivolumab; Retrospective Studies; Uveitis, Anterior; Vemurafenib

Topics: Administration, Oral; Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Protein Structure, Tertiary; Purines; Structure-Activity Relationship; Transplantation, Heterologous

Osimertinib is a potent, highly selective, irreversible inhibitor of epidermal growth factor receptor (EGFR) and T790M resistance mutation. In vitro metabolism data suggested osimertinib is a substrate of cytochrome P450 (CYP)3A4/5, a weak inducer of CYP3A, and an inhibitor of breast cancer resistance protein (BCRP). A combination of in vitro data, clinical pharmacokinetic data, and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib. The model predicted the observed monotherapy concentration profile of osimertinib within 1.1-fold, and showed good predictability (within 1.7-fold) to the observed peak plasma concentration (C

Topics: Acrylamides; Aniline Compounds; Area Under Curve; Computer Simulation; Cytochrome P-450 CYP3A; Drug Dosage Calculations; Drug Interactions; Humans; Itraconazole; Models, Theoretical; Neoplasms; Rifampin; Rosuvastatin Calcium; Simvastatin

We report the successful treatment of the patient with osimertinib 80 mg/day following disease progression and a discordance in the detection of a mechanism of resistance epithelial growth factor receptor (EGFR) T790 M between liquid biopsy and tissue biopsy methods.. A 57-year-old Hispanic male patient initially diagnosed with an EGFR 19 deletion positive lung adenocarcinoma and clinically responded to initial erlotinib treatment. The patient subsequently progressed on erlotinib 150 mg/day and repeat biopsies both tissue and liquid were sent for next-generation sequencing (NGS). A T790 M EGFR mutation was detected in the blood sample using a liquid biopsy technique, but the tissue biopsy failed to show a T790 M mutation in a newly biopsied tissue sample. He was then successfully treated with osimertinib 80 mg/day, has clinically and radiologically responded, and remains on osimertinib treatment after 10 months.. Second-line osimertinib treatment, when administered at 80 mg/day, is both well tolerated and efficacious in a patient with previously erlotinib treated lung adenocarcinoma and a T790 M mutation detected by liquid biopsy.

Topics: Acrylamides; Alleles; Amino Acid Substitution; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Liquid Biopsy; Lung Neoplasms; Magnetic Resonance Angiography; Male; Middle Aged; Mutation; Neoplasms; Piperazines; Protein Kinase Inhibitors; Tomography, X-Ray Computed

Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; ErbB Receptors; Female; Humans; Mice; Mice, Nude; Mutation; Neoplasms; Phenylenediamines; Piperazines; Protein Kinase Inhibitors; Signal Transduction; Transplantation, Heterologous

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Clinical Trials, Phase I as Topic; Computer Simulation; Disease Progression; Drug Administration Schedule; Drug Interactions; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Models, Biological; Neoplasms

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.

Topics: Acrylamides; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Feeder Cells; Fluorescent Antibody Technique; Gene Expression; High-Throughput Screening Assays; Humans; Keratin-18; Keratin-8; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Neoplasms; Piperazines; Precision Medicine; Primary Cell Culture; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tumor Cells, Cultured

AZD9291, a T790M specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated impressive response rates in tumours harbouring the EGFR T790M resistance mutation. Emergence of resistance to AZD9291 has been shown to occur through several different mechanisms including the development of new mutations (e.g. C797S) in the EGFR tyrosine kinase domain. We studied two patients with paired tumour biopsies and blood samples pre- and post-progression on AZD9291 to explore possible resistance mechanisms. Pre- and Post-AZD9291 tumour biopsies as well as serial plasma samples were collected from two patients on the AURA clinical study (AZD9291 First Time in Patients Ascending Dose study). Droplet digital PCR (ddPCR) assays were used to quantify T790M, the driver EGFR mutation, and the C797S mutation in genomic DNA from paired tumour biopsies and plasma cell-free DNA. In the first patient, both EGFR T790M and L858R became undetectable in the plasma within 1 month after treatment with AZD9291. However, the T790M and the original L858R mutation re-emerged with radiologically confirmed resistance to AZD9291. In patient two, the levels of T790M were undetectable at the time of radiological resistance to AZD9291 but increasing levels of the original EGFR exon 19 deletion was detected. MET amplification was detected in a biopsy performed on progression. The EGFR C797S mutation was not detected in either patient at the time of relapse. ddPCR of cell free DNA enables real time monitoring of patients on 3rd generation TKIs. As resistance mechanisms are variable, monitoring levels of the initial activating EGFR mutation may facilitate more reliable detection of progression.

Topics: Acrylamides; Aged; Amino Acid Substitution; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Codon; DNA, Neoplasm; Drug Resistance, Neoplasm; ErbB Receptors; Female; Genetic Variation; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Neoplasms; Protein Kinase Inhibitors; Tomography, X-Ray Computed; Treatment Outcome

In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI, could reverse ABC transporter-mediated MDR. The results showed that, at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [³H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3 µM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at the transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically-approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic stategy in ABCB1-positive drug resistant cancers.

Topics: Acrylamides; Aniline Compounds; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Mutation; Neoplasms; Piperazines