pci-32765 and Lung-Neoplasms

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalent inhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting the covalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized the treatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical and financial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in the field. Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlights the broad opportunity to deliver a new generation of breakthrough therapies.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Phosphotransferases; Protein Kinase Inhibitors

Ibrutinib is an orally administered inhibitor of Bruton's tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited within neuroendocrine neoplasms (NENs) where they stimulate angiogenesis and tumor growth. Ibrutinib inhibits mast cell degranulation and has been associated with regression of tumors in a mouse insulinoma model.. A prospective, phase II trial evaluated patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs) who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560 mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. The primary endpoint was objective response rate.. Twenty patients were enrolled on protocol from November 2015 to December 2017 (15 advanced GI/lung NENs and 5 pNENs). No patient reached an objective response. Median PFS was 3.0 months. A total of 44 drug-related adverse events (AEs) were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs, and 1 patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment.. Ibrutinib does not show significant evidence of activity in well-differentiated gastroenteropancreatic and lung NENs.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Carcinoid Tumor; Female; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Treatment Failure

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.

Topics: Acrylamides; Adenine; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Interleukin-6; Laminin; Lung Neoplasms; Mutation; Piperidines

We describe the case of a 70-year-old never smoker with chronic lymphocytic leukaemia, treated with single agent ibrutinib therapy. Chest imaging noted nodular change and mediastinal lymphadenopathy, which showed avid uptake on positron emission tomography and guided subsequent biopsies (bronchoscopy using endobronchial ultrasound, mediastinoscopy). Despite negative aspergillus blood immunology tests, he was found to have invasive aspergillosis, which is a known risk with ibrutinib therapy. He has since been successfully treated with antifungal therapy.

Topics: Adenine; Aged; Antifungal Agents; Bronchoscopy; Humans; Lung Neoplasms; Macrophages; Male; Mediastinoscopy; Mediastinum; Neoplasm Staging; Piperidines

Topics: Adenine; Adenocarcinoma of Lung; Aged; ErbB Receptors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Male; Neoplasms, Second Primary; Piperidines; Protein Kinase Inhibitors

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is rare among lung neoplasia cases, representing only 0.5%-1% of newly diagnosed primary lung lymphoma. MALT lymphoma with relapsed refractory and malignant transformation is highly heterogeneous and consensus therapy remains undetermined. We report a 55 year-old woman with a 3 year history of primary pulmonary MALT lymphoma confined to the lung presenting with massive pleural effusion. After two cycles of R-CHOP and six cycles of R2-CHOP, pleural effusion disappeared but the pulmonary mass remained persistent. Second-line therapies R2-GemOx failed to make any substantial improvement. Core-needle puncture biopsy of the pulmonary mass was obtained and pathological testing revealed transformed diffuse large B-cell lymphoma of germinal center B-cell subtype. Next-generation sequencing confirmed BN2 subtype. The mass showed no reduction after three cycles of R-MINE, following which the BTK inhibitor ibrutinib was administered to this patient. Unfortunately, after two months of ibrutinib treatment, the patient rapidly developed an enlarged mass and hyperprogressive disease, to which she subsequently succumbed.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Cyclophosphamide; Deoxycytidine; Doxorubicin; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Lung Neoplasms; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Oxaliplatin; Piperidines; Prognosis; Rituximab; Vincristine

Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B-cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti-cancer activity of ibrutinib against solid tumors, such as non-small cell lung cancer (NSCLC), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr-7 exhibited superior anti-cancer activity to ibrutinib, especially against epithelial growth factor receptor (EGFR) wild-type NSCLC cell lines. Ibr-7 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (mTORC1)/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti-cancer activity of Ibr-7 towards NSCLC. Ibr-7 was shown to overcome the elevation of Mcl-1 caused by ABT-199 mono-treatment, and thus exhibited a significant synergistic effect when combined with ABT-199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr-7, which exhibits enhanced anti-cancer activity against NSCLC cells as compared with the parental compound.

Topics: Adenine; Animals; Antineoplastic Agents; Apoptosis; Autoantigens; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Drug Synergism; ErbB Receptors; Female; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Ribonucleoproteins; Ribosomal Protein S6; Signal Transduction; SS-B Antigen; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays

Topics: Adenine; Biopsy; Cough; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Radiography, Thoracic; Salvage Therapy; Sinusitis; Tomography, X-Ray Computed; Treatment Outcome

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; ErbB Receptors; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Nude; Molecular Docking Simulation; Piperidines; Point Mutation; Protein Conformation; Protein Kinase Inhibitors; Rats, Sprague-Dawley

Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2.56, solubility in water≈0.1mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Conformation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Structure-Activity Relationship

Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Mice; Molecular Docking Simulation; Point Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

The new capability to generate mimicking chemical analogues and perform mass screenings of candidate drugs has been tested on B-cell receptor signalling, a driver of B-cell malignancies. These efforts have identified ibrutinib as a potent inhibitor of Bruton's tyrosine kinase. As the clinical use of ibrutinib increases, continued vigilant monitoring for rare adverse events is prudent, including the development of secondary malignancies. To date, the most common reported secondary malignancy is non-melanoma skin cancer; however, we present a case of secondary primary lung adenocarcinoma becoming clinically apparent shortly after initiating therapy with ibrutinib. Our patient had a sudden regression of the tumour with discontinuance of ibrutinib, and based on our understanding of paradoxical tumour growth caused by tyrosine kinase inhibitors it is our hypothesis that the complex multikinase activity of ibrutinib may stimulate tumour growth by targeting a subset of protein kinases critical for growth in some cancer cells.

Topics: Adenine; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Humans; Lung; Lung Neoplasms; Male; Piperidines; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 μM), Ibrutinib exhibited less efficient binding (Kd: 0.18 μM). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix-out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC.

Topics: Acrylamides; Adenine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; ErbB Receptors; Humans; Lung Neoplasms; Molecular Conformation; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M 'gatekeeper' mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib's effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC.

Topics: Adenine; Animals; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Immunoenzyme Techniques; Lung Neoplasms; Mice; Mice, Nude; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non-small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan-Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors.

Topics: Adenine; Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Methionine; Mice; Mutation; Piperidines; Pyrazoles; Pyrimidines; Quinazolines; Threonine

Topics: Adenine; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Approval; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptor Protein-Tyrosine Kinases; United States; United States Food and Drug Administration