Chronicles of EGFR Tyrosine Kinase Inhibitors: Targeting EGFR C797S Containing Triple Mutations

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.     

Two minor chalcone acetylglycosides from the roots extract of <Emphasis Type="Italic">Glycyrrhiza uralensis</Emphasis>

An extensive phytochemical investigation on the roots of Glycyrrhiza uralensis led to the isolation of two new minor chalcone acetylglycosides, i.e., 6″-O-acetylisoliquiritin (1) and 6″-O-acetylneoisoliquiritin (2), including 16 kinds of known constituents (3–18) of flavonoids, chalcones and triterpene saponins. The chemical structures of 1 and 2 were established by spectroscopic analyses of them, particularly by the aid of two-dimensional NMR experiments, COSY, DEPT, HSQC and HMBC. Some isolated components except 1 and 2 exhibited significant inhibitory effects on the proliferation of cultured tumor cell lines, such as A549, SK-OV-3, A-498, and HCD15, in vitro.     

Outcomes of a culturally responsive health promotion program for elderly Korean survivors of gastrointestinal cancers: A randomized controlled trial

This single-blind, prospective, randomized controlled trial was designed to evaluate the effects of a culturally responsive health promotion program for elderly Korean (CHP-K) survivors of gastrointestinal (GI) cancers. The program consisted of 8 weeks of Qi exercise and face-to-face counseling on physical and psychological factors. A total of 63 Korean GI cancer survivors, aged ≥65 years, who had completed their active cancer treatment, were recruited from a cancer center in South Korea. Outcomes included the amount of exercise, body weight, BMI, the Patient Generated Subjective Global Assessment scale, the M.D. Anderson Symptom Inventory, and self-efficacy and self-esteem scales. Repeated measures MANCOVA revealed a significant difference over time between the groups (Wilks' Lambda F_1,62 = 5.361, p = 0.007). Univariate RM-ANCOVA for each outcome measure revealed statistically significant differences between groups. These results suggested that the participation in the CHP-K may have enhanced the health of elderly Korean GI cancer survivors.     

Utilizing the Intrinsic Thermal Instability of Swedenborgite Structured YBaCo4O7+δ as an Opportunity for Material Engineering in Lithium-Ion Batteries by Er and Ga Co-Doping Processes

We firstly introduce Er and Ga co-doped swedenborgite-structured YBaCo₄O_7+δ (YBC) as a cathode-active material in lithium-ion batteries (LIBs), aiming at converting the phase instability of YBC at high temperatures into a strategic way of enhancing the structural stability of layered cathode-active materials. Our recent publication reported that Y_0.8Er_0.2BaCo_3.2Ga_0.8O_7+δ (YEBCG) showed excellent phase stability compared to YBC in a fuel cell operating condition. By contrast, the feasibility of the LiCoO₂ (LCO) phase, which is derived from swedenborgite-structured YBC-based materials, as a LIB cathode-active material is investigated and the effects of co-doping with the Er and Ga ions on the structural and electrochemical properties of Li-intercalated YBC are systemically studied. The intrinsic swedenborgite structure of YBC-based materials with tetrahedrally coordinated Co²⁺/Co³⁺ are partially transformed into octahedrally coordinated Co³⁺, resulting in the formation of an LCO layered structure with a space group of R-3m that can work as a Li-ion migration path. Li-intercalated YEBCG (Li[YEBCG]) shows effective suppression of structural phase transition during cycling, leading to the enhancement of LIB performance in Coulombic efficiency, capacity retention, and rate capability. The galvanostatic intermittent titration technique, cyclic voltammetry and electrochemical impedance spectroscopy are performed to elucidate the enhanced phase stability of Li[YEBCG].     

A combined QM/MM approach to protein--ligand interactions: polarization effects of the HIV-1 protease on selected high affinity inhibitors

HIV-1 protease inhibitors are one of the two widely used therapeutic agents for the treatment of HIV-infected patients. The investigation of HIV-1 protease-inhibitor interactions can provide further insight for developing new compounds that are still required due to the growing problem of drug resistance. To this end, a combined QM/MM approach was used to determine electrostatic and polarization interactions on three high affinity inhibitors, nelfinavir, mozenavir, and tipranavir. The present computational results show that explicit treatment of the polarization effect is particularly important since it can contribute as much as one-third of the total electrostatic interaction energy. Further, an amino acid decomposition analysis was applied to determine contributions of individual residues to the enzyme--inhibitor interactions. It was found that the 4-hydroxy-dihydropyrone substructure of tipranavir is especially suited for extended charge delocalization by interacting with the catalytic aspartates and isoleucines of the HIV-1 protease. The calculated electron density difference maps reaffirm and provide a means of visualizing these results.     

NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs.