Abstract The introduction of novel treatments for Multiple myeloma (MM), particularly proteasome inhibitors (PI) such as bortezomib (BTZ), has greatly improved outcomes. However, many patients ...eventually experience relapse. Therefore, new approaches for managing patients with resistance to PI should be explored. The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that is activated in response to both intrinsic and extrinsic stresses. Stresses are sensed by four specialized kinases: HRI, PERK, PKR, and GCN2, which converge on the phosphorylation of eIF2α. This phosphorylation triggers the translation of ATF4, thus promoting cell survival and homeostasis. Recent studies investigating the contribution of the four ISR kinases in overcoming resistance to PI treatment, have revealed the potential of a selective GCN2 inhibitor to overcome this resistance. Here, we observed that PI simultaneously induced mitochondrial stress, ER stress, and amino acid starvation, leading to the activation of HRI, PERK, and GCN2, respectively. However, the contribution of crosstalk among ISR kinases has not been considered thus far. To gain a comprehensive understanding of ISR kinases in BTZ resistance, we generated single or combination patterns of double and triple KO of the four ISR kinases and reevaluated their contribution to BTZ treatment. Sensitivity screening using the HAP1 single, double, and triple KO cell library showed that HRI primarily, and to a lesser extent, PERK and GCN2, contribute to BTZ resistance. Consistent with the HAP1 KO screening, MM cell line-derived KO cells revealed a similar dependency on these three kinases. Building upon our observation of the significance of the HRI/PERK/GCN2 triple kinase, we developed a novel and orally available small molecule, CRD-1367799, which inhibits these triple kinases in cells. CRD-1367799 effectively dampened the activity of these ISR kinases, leading to a complete inhibition of eIF2α phosphorylation and ATF4 activation. Additionally, we observed a distinct anti-growth effect when combined with BTZ in vitro and in vivo, which was not replicated by the GCN2 or PERK-selective inhibitor. Furthermore, we uncovered the mechanism of cell death induction in combination with proteasome inhibitors. Notably, the apoptosis inducers NOXA and CHOP were upregulated, but the mechanism did not seem to rely on previously known processes such as ATF4-mediated transcriptional induction. In summary, our novel findings on the contribution of the triple ISR kinase provides us with new insights for overcoming resistance to proteasome inhibitors with HRI/PERK/GCN2 inhibitor. To the best of our knowledge, the use of a triple kinase inhibitor in this context has not been reported thus far, making CRD-1367799 a new therapeutic strategy for MM with PI. Citation Format: Yasumichi Inoue, Koki Hikami, Shunsuke Ebara, Midori Sugiyama, Robert Oda, Akio Mizutani, Misaki Yoshida, Hiroko Yamakawa, Shigehiro Yagishita, Akinobu Hamada, Hidetoshi Hayashi, Masaki Ri, Shinsuke Iida, Daisuke Morishita. Novel inhibitor targeting triple integrated stress response kinase HRI, PERK, and GCN2 provides new insights into overcoming resistance to proteasome inhibitors in multiple myeloma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1233.
Footprint of shape resonance is observed in angle-resolved rescattering photoelectron spectra (RPS) of CO sub(2) induced by intense femtosecond laser pulses. The rescattering spectra are compared ...with theoretical calculations of the differential cross sections (DCSs) of electron scattering by CO super(+) sub(2). The RPS and DCSs show a clear dip where collision momentum of electron is around 1.2 atomic unit. This dip is interpreted theoretically as the interference of two different shape resonances, where electrons in the continuum states are trapped by the potential barrier of the electron-ion scattering potential.
Footprint of shape resonance is observed in angle-resolved rescattering photoelectron spectra (RPS) of CO2 induced by intense femtosecond laser pulses. The rescattering spectra are compared with ...theoretical calculations of the differential cross sections (DCSs) of electron scattering by CO+2. The RPS and DCSs show a clear dip where collision momentum of electron is around 1.2 atomic unit. This dip is interpreted theoretically as the interference of two different shape resonances, where electrons in the continuum states are trapped by the potential barrier of the electron-ion scattering potential.
We extract large-angle elastic differential cross sections (DCSs) for electrons scattering from partially aligned O+2 and CO+2 molecules using rescattering photoelectrons generated by infrared laser ...pulses. The extracted DCSs are in good agreement with those calculated theoretically, demonstrating that accurate DCSs for electron-ion scattering can be extracted from the laser-induced rescattering spectra.
Synopsis We have measured angle-resolved rescattering photoelectron spectra induced by ultrashort intense near-IR laser pulses at 1200-1650 nm. From the spectra, we have extracted field-free ...electron-ion differential scattering cross sections and compared them with theoretical calculations.
We report the case of a 61-year-old man with type B Wolff-Parkinson-White (WPW) syndrome associated with a right atrioventricular (AV) accessory pathway and concomitant mitral stenosis, who underwent ...successful operative treatment by simultaneous surgery. His preoperative course had been characterized by cardiac failure and repeated episodes of atrial tachyarrhythmia, in the form of fibrillation and flutter, which were difficult to control by conventional medication. Preoperative electrocardiograms (ECGs) had suggested that the accessory pathway was located in the right posterior to posteroseptal wall; however, at the time of surgery, epicardial electrophysiological mapping with sock electrodes revealed a preexcitation area in the AV groove at the lateral right margin of the heart. This discrepancy was thought to have been due to the presence of mitral stenosis or multiple accessory pathways. Thus, division and cryoablation of the accessory pathway by an endocardial approach, in addition to mitral valve replacement, were performed under cardiopulmonary bypass. His postoperative course was uneventful, and subsequent ECGs revealed that the delta waves had disappeared. The successful outcome of this patient demonstrates the effectiveness of simultaneous surgery for WPW syndrome associated with valvular disease.
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