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Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing EGFR or BRAF mutations or activating ALK, ROS1 or NTRK translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis.

Lung sarcomatoid carcinoma is a rare tumor. We report a rare case of pancreatic metastasis in a 76-year-old man with lung sarcomatoid carcinoma. Right upper lobectomy was performed, and the patient was diagnosed with pulmonary sarcomatoid carcinoma with a MET exon 14 skipping mutation. A biopsy of the pancreatic lesion subsequently revealed pancreatic metastasis. A MET exon 14 skipping mutation was confirmed, and the patient was treated with a MET tyrosine kinase inhibitor and maintained a complete response for 2 years. Lung sarcomatoid carcinoma rarely metastasizes to the pancreas and can be adequately treated with a MET tyrosine kinase inhibitor.

Introduction: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients. Materials and methods: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction. Results: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57–1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43–1.50] to 2.19 [95 % CI, 2.12–2.25]. Discussion/Conclusion: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.

Objective: To investigate the optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Patients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 were analyzed retrospectively, and were categorized into three groups according to the primary treatment: chemoradiotherpy (CRT) (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), and EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. Results: A total of 104, 105, and 231 patients were categorized into groups 1, 2, and 3, respectively. After IPTW adjustment, the median PFS for each group was 12.4, 26.2, and 16.2 months (log-rank P < 0.001), and the median OS was 51.0, 67.4 and 49.3 months (log-rank P = 0.084), respectively. Compared with those in group 1, patients in group 2 had significantly improved PFS [adjusted hazard ratio HR (aHR), 0.40; 95% confidence interval (CI): 0.29, 0.54; P < 0.001] and OS (aHR, 0.61; 95% CI: 0.38, 0.98; P = 0.039). Patients in group 3 had prolonged PFS (aHR, 0.66; 95% CI: 0.50, 0.87; P = 0.003), but not OS (aHR, 0.90; 95% CI: 0.62, 1.32; P = 0.595). Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings. Conclusions: EGFR-TKIs after chemoradiation or combined with radiation alone correlated with the longest PFS and OS (versus CRT or TKIs alone) in patients with EGFR-mutant unresectable LA-NSCLC. Well-designed prospective trials were warranted.

Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing EGFR or BRAF mutations or activating ALK, ROS1 or NTRK translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen., Competing Interests: Declaration of Competing Interest The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients., Materials and Methods: This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction., Results: 34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25]., Discussion/conclusion: In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

A bioluminescent immunoassay system was developed to determine serine/threonine protein kinase activity using an aequorin-labeled monoclonal antibody and a synthetic peptide as the substrate. A monoclonal antibody against the synthetic phosphorylated serine peptide (K9P peptide) of histone H3 (19 amino acid residues), referred to as the H3S10P antibody, was chemically conjugated to maleimide-activated aequorin to prepare aequorin-labeled H3S10P (AQ-S-H3S10P). For the serine/threonine kinase assay, a non-phosphorylated serine peptide (K9C peptide) coated on a microplate was incubated with serine/threonine protein kinase in the presence of ATP and Mg 2+ . The resulting phosphorylated K9C peptides (K9P peptide) were identified using AQ-S-H3S10P. Thus, after the removal of unbound AQ-S-H3S10P though washing, the serine/threonine kinase activity was determined by the luminescence activity of aequorin from AQ-S-H3S10P bound to the K9P peptide. This assay system, in combination with the K9C peptide and AQ-S-H3S10P, could be used to screen inhibitors of various serine/threonine protein kinases in general., Competing Interests: Declaration of competing interest J. Sato and S. Inouye are employees in JNC Corporation. H. Onogi, and N. Nomura are employees in KinoPharma, Inc. M. Hagiwara declares that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Older patients (≥65 years old) make up the majority of the cancer population. Older patients seem to experience more adverse events (AEs) from protein kinase inhibitors (PKIs) in clinical practice. Yet they are underrepresented in clinical trials. We aimed to evaluate whether age-related safety differences were described at authorization of PKIs. Representation of older patients in registration studies was also evaluated., Materials and Methods: European Public Assessment Reports (EPARs) of PKIs authorized between 2010 and 2015 were evaluated for the description of age-related safety- and pharmacokinetic differences. The International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use (ICH) E7 guideline was applied to EPARs to assess the representation of older patients. Study results were presented descriptively., Results: Eighteen PKIs with 19 EPARs were analyzed. Age-related safety differences were described in 14 out of 19 EPARs, and age-related pharmacokinetic differences in 1 out of 19 EPARs. More than 100 older patients were included in half of the studies. Older patients were not excluded solely by age, although other inclusion and exclusion criteria negatively influenced enrollment of older patients. None of the PKIs met all criteria from the ICH E7 guideline., Discussion: Age-related safety differences are described for most PKIs. Older patients were underrepresented in PKI registration studies. Adequate representation of older patients in clinical trials for PKIs is vital, since they make up most of the cancer population., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oncotherapeutic agents can cause a wide range of liver injuries from elevated liver functions tests to fulminant liver failure. In this review, we emphasize a newer generation of drugs including immune checkpoint inhibitors, protein kinase inhibitors, monoclonal antibodies, and hormonal therapy. A few conventional chemotherapy agents are also discussed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hormone-sensitive lipase partially purified from adipose tissue of laying hens was markedly activated by cyclic AMP-dependent protein kinase. Activation was approximately 4-fold (ranging up to as great as 10-fold) compared with the much lower degree of activation obtained with analogous preparations from rat and human adipose tissues (59 and 86%, respectively). The partially purified preparations contained adequate endogenous protein kinase activity to effect complete activation with addition of cyclic AMP, ATP, and Mg2+. Activation was blocked by protein kinase inhibitor (from rabbit skeletal muscle) but could be restored fully by addition of excess exogenous protein kinase (from bovine skeletal muscle). The fully activated lipase was slowly deactivated by dialysis at 4°C and then rapidly and almost fully reactivated by addition of cyclic AMP and ATP–Mg2+. Reactivation was blocked by protein kinase inhibitor. This deactivation–reactivation cycle was rapid at 23°C with dialysis against charcoal and could be demonstrated repeatedly using a single preparation. The reversible deactivation of protein kinase-activated enzyme is presumed to reflect the action of a lipase phosphatase. Lipase prepared from tissue previously exposed to glucagon yielded a much smaller degree of activation than lipase prepared from tissue not exposed to the lipolytic hormone, indicating that the physiological hormone-induced activation is probably similar to or identical with the protein kinase activation demonstrated in the cell-free preparations. Under the conditions of assay used, the partially purified lipase fraction contained diglyceride, monoglyceride, and lipoprotein lipase activities. However, treatment with cyclic AMP-dependent protein kinase had virtually no effect on these lipase activities.

Research Question: Endometriosis is a common gynaecological disease defined by the presence of endometrium-like tissue outside the uterus. This complex disease, often accompanied by severe pain and infertility, causes a significant medical and socioeconomic burden; hence, novel strategies are being sought for the treatment of endometriosis. Here, we set out to explore the cytotoxic effects of a panel of compounds to find toxins with different efficiency in eutopic versus ectopic cells, thus highlighting alterations in the corresponding molecular pathways., Design: The effect on cellular viability of 14 compounds was established in a cohort of paired eutopic and ectopic endometrial stromal cell samples from 11 patients. The biological targets covered by the panel included pro-survival enzymes, cytoskeleton proteins, the proteasome and the cell repair machinery., Results: Protein kinase inhibitors GSK690693, ARC-775 and sorafenib, proteasome inhibitor bortezomib, and microtubule-depolymerizing toxin monomethyl auristatin E were more effective in eutopic cells. In contrast, 10 µmol/l of the anthracycline toxin doxorubicin caused cellular death in ectopic cells more effectively than in eutopic cells. The large-scale sequencing of mRNA isolated from doxorubicin-treated and control cells indicated different survival strategies in eutopic versus ectopic endometrium., Conclusions: Overall, the results confirm evidence of large-scale metabolic reprogramming in endometriotic cells, which underlies the observed differences in sensitivity towards toxins. The enhanced efficiency of doxorubicin interfering with redox equilibria and/or DNA repair mechanisms pinpoints key players that can be potentially used to selectively target ectopic lesions in endometriosis., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Rho-associated serine/threonine kinases (ROCKs) are principal regulators of the actin cytoskeleton that regulate the contractility, shape, motility, and invasion of cells. We explored the relationships between structure and anti-ROCK2 activity in a group of purine derivatives substituted at the C6 atom by piperidin-1-yl or azepan-1-yl groups. Structure-activity relationship (SAR) analyses suggested that anti-ROCK activity is retained, and may be further increased, by substitution of the parent compounds at the C2 atom or by expansion of the C6 side chain. These inhibitors of ROCK can reach effective concentrations within cells, as demonstrated by a decrease in phosphorylation of the ROCK target MLC, and by inhibition of the ROCK-dependent invasion of melanoma cells in the collagen matrix. Our study may be useful for further optimization of C6-substituted purine inhibitors of ROCKs and of other sensitive kinases identified by the screening of a broad panel of protein kinases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 μM, and of 1  μM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37-50% reduction in foetal mortality, and modulated immune responses; IFNγ levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69-71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed., (Copyright © 2018. Published by Elsevier Ltd.)

High demand for inhibitors regulating the activity of protein kinases has stimulated the quest for high throughput and reliable compound screening assays. Here we introduce a method applying a non-metal photoluminescent probe ARC-Lum(Fluo) for determination of dissociation constants of competitive inhibitors of protein kinases. Employing a single probe instead of a combination of antibody and fluorescent tracer makes the assay simpler, cheaper, and more accurate than several other inhibitor-screening technologies. High affinity (20 pM) and low background signal of the free probe supports the determination of dissociation constants of tight-binding as well as low affinity inhibitors. The calculated lowest K d value that can be accurately determined with the method is 60 fM. We also introduce graphical presentation of the linearized Cheng-Prusoff equation and demonstrate multiple possibilities for its application (deciding upon the assay formats, calculation of the limits of K d determination, etc.). The open toolbox (http://www.ut.ee/medchem/toolbox-fluorescence-probes) is available for creating the map of resolvable affinities if applying the competitive probes at defined assay conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile., Methods: The INPULSIS™ trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged ≥40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1-year before screening, and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing capacity for carbon monoxide of 30-79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George's Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation., Results: Enrolment of 1066 patients in 24 countries was completed in September 2012. Results will be reported in the first half of 2014., Conclusion: The INPULSIS™ trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population., Trial Registration: Registered at ClinicalTrials.gov (identifiers: NCT01335464 and NCT01335477)., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Nitric oxide (NO) and related nitrovasodilators regulate blood pressure by activation of soluble guanylate cyclase, elevation of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (cGPK). Despite the progress of our understanding of the NO/cGMP mediated vasorelaxation, partly through conventional cGPK knock-out mice, the role of cGPK remains unclear. In particular, the downstream target(s) of the kinase are not well defined. We hypothesized that highly selective inhibitors of cGPK delivered in vivo in adult may elucidate the role of the kinase in vasorelaxation and regulation of blood pressure., Methods and Results: We have adopted a newly developed method of TAT-mediated protein transduction to study NO/cGMP signaling pathways in mice. In vitro, TAT-cGPK inhibitor peptide blocked autophosphorylation of the kinase. The effect of cGPK inhibition on murine blood pressure (BP) was investigated by continuous infusion of 100 μg of the inhibitor into the internal jugular vein over 72 hours. In 8 animals infused with the inhibitor, the mean BP increased by 38 ± 24/31 ± 30 mm Hg (from 108 ± 14/92 ± 19 to 145 ± 13/123 ± 19 mm Hg) whereas in 8 animals injected with either saline (4) or TAT-green fluorescent protein (4), the BP remained the same (from 117 ± 21/101 ± 26 to 119 ± 22/96 ± 30 mm Hg); P=0.001. Ex vivo, using vascular ring assays, NO-dependent relaxation in murine aortas harvested from animals administered with TAT-cGPK inhibitor was inhibited by 25% (sham 76 ± 11%, inhibitor 51 ± 13%)., Conclusion: We demonstrated that highly specific peptide inhibitor of cGPK induced adult murine hypertension through inhibition of nitric oxide mediated relaxation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)