pyrimidinones and Fibrosarcoma

Topics: Fibrosarcoma; Humans; Infant; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Fibrosarcoma; Humans; Indoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones

Blockade of the ERK pathway has antitumor effects against malignant tumor cells. In this study, we investigated the antitumor activity of JTP-70902, a novel specific MEK inhibitor, against human fibrosarcoma cells in which the ERK pathway is constitutively activated. JTP-70902 was synthesized at Japan Tabacco. Human fibrosarcoma HT1080 cells were cultured. JTP-70902 was added at various concentrations. The number of viable cells was counted employing a trypan blue dye exclusion test. Unsynchronized cells were exposed to JTP-70902 for 24 h. The nuclei were stained with propidium iodide. The DNA content was measured using a FACSCalibur flow cytometer. Protein extraction and Western blot analysis were performed. (1) A dose-dependent inhibition of cell growth was observed at concentrations of 10 nM or more. Forty-eight hours after the treatment, the growth of HT1080 cells was completely inhibited by 200 nM JTP-70902. (2) FACS analysis revealed that a 24-h exposure to JTP-70902 increased the population of G1/S phase cells in a dose-dependent manner. (3) The phosphorylation of ERK was inhibited by JTP-70902. Furthermore, after the treatment with JTP-70902, p21WAF1/CIP1 and p27KIP1 protein expression increased and the phosphorylation of RB was reduced. Our results showed that JTP-70902 inhibits cell growth and induces cell cycle arrest in human Ras mutant fibrosarcoma cells. These results indicate that JTP-70902 might be an attractive compound for molecular-targeting chemotherapy for malignant soft tissue tumors with the activation of the Ras-MEK-ERK pathway.

Topics: Antineoplastic Agents; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Drug Evaluation, Preclinical; Fibrosarcoma; G1 Phase; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Protein Kinase Inhibitors; Pyrimidinones; S Phase; Sulfonamides; Time Factors; Tumor Cells, Cultured

Since pyrimidinone compounds induce interferon production in several animal species and have potent antivirus activities, it appeared important to determine whether these compounds could also induce antitumor activities in their recipients. Pyrimidinone compounds 2-amino-5-bromo-6-methyl-4-pyrimidinone (ABMP), 2-amino-5-brome-6-phenyl-4-pyrimidinone (ABPP), and 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) were studied for their activities against artificial lung metastases of the weakly immunogenic spontaneous fibrosarcoma NFSa, the moderately immunogenic spontaneous mammary carcinoma MCa-K, and the strongly immunogenic 3-methylcholanthrene-induced fibrosarcoma FSa syngeneic to inbred C3Hf/Kam mice. In addition, the therapeutic efficacy of ABPP and AIPP was also determined against spontaneous lung metastases of NFSa. ABPP and AIPP given ip at 250 mg/kg for 2 or 3 consecutive days before or after iv inoculatin of NFSa, FSa, or MCa-K cells greatly reduced the number of tumor nodules developed in the lungs. ABMP, however, was considerably less effective. ABPP and AIPP were also effective in therapy of spontaneous lung metastases of NFSa, especially when these compounds were given before surgical removal of the primary tumor. Neither ABPP nor AIPP was effective against tumor nodules growing in whole-body irradiated (WBI) mice, but both protected mice against enhancement of lung metastasis formation induced by exposure to whole-body irradiation. ABPP was more effective than AIPP in inducing production of interferon in normal mice. When treated with ABPP, WBI mice, however, were unable to produce interferon. These results show that 6-phenyl-pyrimidinone compounds induce strong antitumor activities in mice, which correlated with neither tumor immunogenicity nor the ability of these agents to induce interferon, but which depended on the immune status of the tumor host.

Topics: Animals; Cytosine; Dose-Response Relationship, Drug; Fibrosarcoma; Immunity, Innate; Interferon Inducers; Interferons; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Pyrimidinones; Time Factors; Whole-Body Irradiation