Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead.

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRasG12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRasG12C have shown promising efficacy against cancers harboring KRASG12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRasG12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRasG12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRasG12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R.

Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.

Postharvest biochemical characteristics and ultrastructure of Coprinus comatus.

BACKGROUND: Coprinus comatus is a novel cultivated edible fungus, hailed as a new preeminent breed of mushroom. However, C. comatus is difficult to keep fresh at room temperature after harvest due to high respiration, browning, self-dissolve and lack of physical protection. METHODS: In order to extend the shelf life of C. comatus and reduce its loss in storage, changes in quality, biochemical content, cell wall metabolism and ultrastructure of C. comatus (C.c77) under 4 °C and 90% RH storage regimes were investigated in this study. RESULTS: The results showed that: (1) After 10 days of storage, mushrooms appeared acutely browning, cap opening and flowing black juice, rendering the mushrooms commercially unacceptable. (2) The activity of SOD, CAT, POD gradually increased, peaked at the day 10, up to 31.62 U g-1 FW, 16.51 U g-1 FW, 0.33 U g-1 FW, respectively. High SOD, CAT, POD activity could be beneficial in protecting cells from ROS-induced injuries, alleviating lipid peroxidation and stabilizing membrane integrity. (3) The activities of chitinase, ß-1,3-glucanase were significantly increased. Higher degrees of cell wall degradation observed during storage might be due to those enzymes' high activities. (4) The fresh C. comatus had dense tissue and every single cell had the number of intracellular organelles which structure can be observed clearly. After 10 d storage, the number of intracellular organelles was declined and the structure was fuzzy, the nucleus disappeared. After 20 d storage, C. comatus's organization was completely lost, many cells were stacked together and the cell wall was badly damaged.

Comparative study on the composition of four different varieties of garlic.

Garlic is used as a medicinal seasoning worldwide. The aim of this work was to compare four varieties of garlic: 'Taicangbaipi', 'Ershuizao', 'Hongqixing', and 'Single-clove'; among them, 'Ershuizao' and 'Hongqixing' are unique to the Sichuan Province of China. Firstly, soluble sugar, starch, and the protein content of the garlic were analysed. There was more soluble sugar in 'Single-clove', total starch in 'Hongqixing', and protein content in 'Ershuizao' relative to the other three varieties, respectively. Gas chromatography-mass spectrometry analysis showed that 'Ershuizao' and 'Hongqixing' contained high levels of 5-hydroxymethylfurfural, which has antitumor, antioxidant, and cytoprotective effects. Indeed, the extracts from these two types of garlic were more effective at inhibiting tumour growth than that from the others. Moreover, the sulphide content and antimicrobial effects of 'Ershuizao' and 'Hongqixing' garlic were also higher than those of the other two types of garlic. In addition, changes observed in the membrane permeability and protein leakage suggest that the antimicrobial activity of the 'Ershuizao' and 'Hongqixing' extracts may be due to the destruction of the structural integrity of the cell membranes, leading to cell death.

Characterization of wheat - Psathyrostachys huashanica small segment translocation line with enhanced kernels per spike and stripe rust resistance.

Psathyrostachys huashanica Keng (2n = 2x = 14, NsNs), a distant wild relative of common wheat, possesses rich potentially valuable traits, such as disease resistance and more spikelets and kernels per spike, that could be useful for wheat genetic improvement. Development of wheat - P. huashanica translocation lines will facilitate its practical utilization in wheat breeding. In the present study, a wheat - P. huashanica small segmental translocation line, K-13-835-3, was isolated and characterized from the BC1F5 population of a cross between wheat - P. huashanica amphiploid PHW-SA and wheat cultivar CN16. Cytological studies showed that the mean chromosome configuration of K-13-835-3 at meiosis was 2n = 42 = 0.10 I + 19.43 II (ring) + 1.52 II (rod). GISH analyses indicated that chromosome composition of K-13-835-3 included 40 wheat chromosomes and a pair of wheat - P. huashanica translocation chromosomes. FISH results demonstrated that the small segment from an unidentified P. huashanica chromosome was translocated into wheat chromosome arm 5DS, proximal to the centromere region of 5DS. Compared with the cultivar wheat parent CN16, K-13-835-3 was highly resistant to stripe rust pathogens prevalent in China. Furthermore, spikelets and kernels per spike in K-13-835-3 were significantly higher than those of CN16 in two growing seasons. These results suggest that the desirable genes from P. huashanica were successfully transferred into CN16 background. This translocation line could be used as novel germplasm for high-yield and, eventually, resistant cultivar breeding.