Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells

Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan-HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)-amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2-amplified gastric cancer cells. Two afatinib-resistant gastric cancer cell lines were established from 2 HER2-amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87-derived resistant cells, whereas it was upregulated in SNU216-derived resistant cells. In the N87-derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216-derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2-driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance

A case of a warfarinized renal cancer patient monitored for prothrombin time-international normalized ratio during methadone introduction

Abstract Background Warfarin, a widely used anticoagulant, interacts with various agents used in palliative care, such as oxycodone, morphine, acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs); however, there are no reports of its interaction with methadone. We report a case of a patient receiving warfarin when methadone was introduced for pain control with monitoring of the prothrombin time-international normalized ratio (PT-INR) and deduced the pharmacological background. Case presentation A 60-year-old male was emergently admitted to our university hospital for the sudden onset of severe back pain. Abdominal CT imaging revealed that the vertebral body of the ninth thoracic vertebra was occupied by bone metastasis and crushed, which caused his back pain. He received warfarin 3.5 mg/day for atrial fibrillation and tapentadol 100 mg p.o. daily for pain relief. The prothrombin time-international normalized ratio (PT-INR) was maintained at >2.2. The patient’s history included diabetes mellitus and hypertension, but his laboratory test was unremarkable with the exception that his eGFR was 34 ml/min. Initially, a fentanyl dermal patch was used instead of tapentadol to avoid interactions with warfarin. We started concomitant administration of oxycodone and 2.4 g/day of acetaminophen while monitoring the PT-INR because acetaminophen increased the PT-INR to 2.93. A continuous intravenous infusion of oxycodone was introduced, in increments of the dose, resulting in an increase of the PT-INR to 3.41, which is required to reduce the dose of warfarin to 1.5 mg. Because of the lack of effective pain relief, methadone was introduced and the dose was gradually increased. The PT-INR was not changed and the dose of warfarin was not changed. An infusion of oxycodone and oral methadone was used to allow the patient to walk in his room, and he was later transferred to the palliative hospital. Conclusions In an oral warfarinized patient, methadone seemed to undergo different metabolism than oxycodone. When warfarin and methadone are used together, we have to consider their interaction by comparing the competitive inhibition of CYP2C9 to the induction of CYP3A4 by methadone, because CYP3A4 metabolize various drugs including oxycodone

Volcanic activity on Io and its influence on the dynamics of the Jovian magnetosphere observed by EXCEED/Hisaki in 2015

Abstract Jupiter’s moon Io, which orbits deep inside the magnetosphere, is the most geologically active object in the solar system. Kurdalagon Patera, a volcano on Io, erupted in 2015 and became a substantial source of Jovian magnetospheric plasma. Based on Earth-orbiting spacecraft observations, Io plasma torus (IPT) exhibited the peak intensity (nearly double) of ionic sulfur emissions roughly 2 month later, followed by a decay phase. This environmental change provides a unique opportunity to determine how the more heavily loaded magnetosphere behaves. Indeed, the extreme ultraviolet spectroscope for exospheric dynamics onboard the Earth-orbiting spacecraft Hisaki witnessed the whole interval via aurora and IPT observations. A simple-minded idea would be that the centrifugal force acting on fast co-rotating magnetic flux tubes loaded with heavier contents intensifies their outward transport. At the same time, there must be increased inward convection to conserve the magnetic flux. The latter could be accompanied by (1) increased inward velocity of field lines, (2) increased frequency of inward transport events, (3) increased inward flux carried per event, or (4) combinations of them. The Hisaki observations showed that the densities of major ions in the IPT increased and roughly doubled compared with pre-eruption values. The hot electron fraction, which sustains the EUV radiation from the IPT, gradually increased on a timescale of days. Pairs of intensified aurora and IPT brightening due to the enhanced supply of hot electrons from the mid-magnetosphere to the IPT upon aurora explosions observed during both quiet and active times, enabled the study of the mid-magnetosphere/IPT relationship. Hisaki observations under active Io conditions showed that: (1) the hot electron fraction in the torus gradually increased; (2) brightening pairs were more intense; (3) the energy supplied by the largest event maintained enhanced torus emission for less than a day; (4) the time delay of a torus brightening from a corresponding aurora intensification was roughly 11 h, that is, the same as during quiet times, suggesting that the inward convection speed of high-energy electrons does not change significantly. Graphical abstract

Development of <i>N</i>‑(4-Phenoxyphenyl)benzenesulfonamide Derivatives as Novel Nonsteroidal Progesterone Receptor Antagonists

We report here development of <i>N</i>-(4-phenoxyphenyl)­benzenesulfonamide derivatives as a novel class of nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are candidates for clinical treatment of multiple diseases, including uterine leiomyoma, endometriosis, breast cancer, and some psychiatric disorders. We found that the benzenesulfonanilide skeleton functions as a novel scaffold for PR antagonists, and we adopted 3-chlorobenzenesulfonyl derivative <b>20a</b> as a lead compound for structural development. Among the synthesized compounds, 3-trifluoromethyl derivative <b>32</b> exhibited the most potent PR-antagonistic activity, with high binding affinity for PR and selectivity over androgen receptor (AR). It is structurally distinct from other nonsteroidal PR antagonists, including cyanopyrrole derivatives, and further modification is expected to afford novel selective PR modulators