Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron–sulfur (Fe–S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

Gastric carcinoma is the third major cause of cancer‐related death in China. Bcl‐2 and other BH3 family proteins are critically important in the process of apoptosis pathway, which may be a promising target. APG‐1252‐M1 specifically connects to Bcl‐2 and Bcl‐xl. The antitumor effect of APG‐1252‐M1 in six gastric cancer cells was identified by the Cell Counting Kit‐8 assay. The expression level of proapoptotic proteins was evaluated by Western blot. Meanwhile, the cell cycle and apoptosis distributions were analyzed by flow cytometry and JC‐1. Xenograft models were used to investigate the roles of APG‐1252‐M1 in suppressing the growth of tumors and enhancing the chemotherapy antitumor effect. The antitumor effect of APG‐1252‐M1 was time‐ and dose‐dependent and acted by initiating apoptosis. The change of cell cycle distribution was not discovered in gastric cancer cells treated with APG‐1252‐M1. APG‐1252‐M1 also exhibited synergy with chemotherapy in vivo. The combined group inhibited xenograft tumor growth more obviously than the other groups. Moreover, Ki‐67 was remarkably decreased in the combination group compared to other groups. In conclusion, APG‐1252‐M1 had a strong antitumor effect by inducing apoptosis and was synergistic with chemotherapy.

Key Points Question Is prophylactic aprepitant therapy combined with palonosetron and dexamethasone effective in preventing nausea and vomiting in women receiving moderately emetogenic chemotherapy? Findings In this randomized phase 3 clinical trial that included 248 women younger than 50 years with no or little alcohol use, the complete response rate in the overall phase for chemotherapy-induced nausea and vomiting was 87% in the aprepitant group vs 67% in the control group. The overall complete response rate was significantly higher in the aprepitant group vs the control group. Meaning Adding aprepitant to palonosetron and dexamethasone was effective in reducing nausea and vomiting for women who received moderately emetogenic chemotherapy.

BackgroundRecent studies have suggested that the lymph node ratio (LNR) is a prognostic indicator for various malignancies. However, LNR has not been evaluated in colorectal liver-only metastasis (CRLM). This study aimed to investigate the prognostic value of LNR in patients with CRLM after curative resection.Patients and methodsWe retrospectively investigated the clinicopathologic features of 154 CRLM patients who underwent curative resection between 2005 and 2015. We classified patients into low and high groups based on their LNR by using the X-tile software. Survival curves were plotted through Kaplan–Meier method and compared by log-rank test. Cox proportional hazards analysis was performed to identify the factors associated with recurrence-free survival (RFS) and overall survival (OS).ResultsThe patients were divided into two groups in which 124 patients were identified as LNR ≤0.33 and 30 patients as LNR >0.33. Compared to low LNR, high LNR was significantly associated with poor 3-year RFS (47.2% vs 16.7%, P=0.001) and OS (72.8% vs 45.3%, P=0.003) rates. Multivariate analysis indicated that the LNR was an independent predictor for 3-year RFS (hazard ratio, 2.124; 95% CI, 1.339–3.368; P=0.001) and OS (HR, 2.287; 95% CI, 1.282–4.079; P=0.005). However, the node (N) stage and lymph node distribution were not significantly associated with the 3-year RFS (P=0.071, P=0.226) or OS (P=0.452, P=0.791) in patients with CRLM.ConclusionThis study demonstrated that LNR was an independent predictor for 3-year RFS and OS in patients with CRLM who underwent curative resection and that its prognostic value was superior to that of N stage and lymph node distribution.