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Nephrotoxicity is a major adverse reaction of cisplatin-based chemotherapy. Organic cation transporter 2 (OCT2) which is located on the basement membrane of human proximal renal tubules is responsible for the renal accumulation of cisplatin and its nephrotoxicity. This study aimed to investigate the protective effect of PPIs to CP-induced nephrotoxicity. Three kinds of PPIs including lansoprazole, omeprazole and rabeprazole (Rab) were co-administrated with CP to mice. In addition, OCT2-overexpressed HEK293, HK-2 and A549 cells were co-incubated with CP and PPIs. The results showed that PPIs can attenuate CP-induced increase of CRE, BUN and histological damage of kidney. Among the three PPIs, Rab was found with a superior protective effect. It significantly reduced the accumulation of CP in OCT2-overexpressed HEK293 cells and in the renal cortex tissues of mice, but not in HK-2 cells. Moreover, Rab reduced the expression levels of cleaved-caspase-3, RIPK1, RIPK3, MLKL and p-MLKL and the apoptosis rate of renal tubular cells induced by CP in vivo, but not in HK-2 cells. However, Rab increased the viability of CP-treated cells in a concentration-dependent manner and attenuated CP-induced apoptosis and necroptosis in OCT2 over-expressed HEK293 cells. Finally, we demonstrated that Rab have no influence on the antitumor effect of CP. In conclusion, Rab attenuate CP-induced nephrotoxicity mainly through inhibiting OCT2-mediated CP uptake, without interfering with its anti-tumor property of inducing apoptosis and necroptosis.

Purpose:In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non–small cell lung cancer (NSCLC).Patients and Methods:In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety.Results:The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0–69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0–9.6 months), and median OS was 12.5 months (95% CI, 8.2–16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%−40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression.Conclusions:Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

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BACKGROUND The FGFR signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Novel FGFR gene fusions may represent candidate targets for the development of tyrosine kinase inhibitors. CASE SUMMARY Herein, we report a patient with colorectal cancer (CRC) harboring a novel FGFR2 fusion gene. A 59-year-old man felt discomfort in his right upper abdomen with loss of appetite for 6 mo. An abdominal computed tomography scan revealed the existence of a space-occupying lesion in the ascending colon. The pathological diagnosis was a poorly differentiated adenocarcinoma. Subsequent biopsy specimen was subjected to next-generation sequencing analysis, and a novel FGFR2-TSC22D1 fusion with complete kinase structure of FGFR2 protein was identified. CONCLUSION We report the first case of CRC harboring FGFR2-TSC22D1, which enriches the FGFR2 fusion spectrum. FGFR2 inhibitors might be effective in the later treatment for this patient.

Necroptosis is defined as a novel programmed cell necrosis that is mediated by receptor interacting serine-threonine protein kinase 1 (RIPK1) and other related signals. Necrosis, apoptosis and inflammation are commonly considered as the leading mechanism in acute kidney injury (AKI) induced by gentamicin (GEN), which is a useful antibiotic for treating the infection of Gram-negative bacterial. However, the necroptosis in the pathogenesis of GEN-induced AKI is unknown. In this study, to investigate the process and function of necroptosis in GEN-induced AKI, NRK-52E and HK-2 cells and SD rats were used as the models. The necroptosis-related proteins, including RIPK1, RIPK3, mixed lineage kinase domain-like (MLKL) and phosphorylated MLKL (p-MLKL), were all increasing time-dependently when GEN was continuously given. By using the RIPK1 inhibitor necrostatin-1 (NEC-1) and RIPK3 inhibitor (CPD42), the GEN-induced toxicity of tubular cells was alleviated. Moreover, it was validated that GEN-induced cell apoptosis and inflammation were attenuated after treating with NEC-1 or CPD42, both in vivo and in vitro. When MLKL was knocked down by siRNA, NEC-1 and CPD42 can not further protect the damage of tubular cells by GEN. Although the using of pan-caspase inhibitor Z-VAD significantly decreased GEN-induced apoptosis, it enhanced necroptosis and slightly promoted the decreased cell viability in GEN-treated cells, with the protective effects weaker than NEC-1 or CPD42. Finally, in vitro minimum inhibitory concentration (MIC) tests and bacteriostatic ring studies showed that NEC-1 did not interfere with the antibiotic effects of GEN. Thus, suppressing necroptosis can serve as a promising strategy for the prevention of GEN-induced nephrotoxicity.

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.