Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma.

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

Prophylactic Effect of Nitric Oxide Donors on Rat Models of EGFR Inhibitor‒Induced Cutaneous Toxicities.

EGF receptor (EGFR) inhibitors have been established as first-line standard-of-care therapies for nonsmall cell lung cancer but are frequently accompanied by adverse dermatological effects, in particular, acneiform rash. There is no effective clinical intervention, partially because of its poorly understood etiology. In this study, we show that inhibition of EGFR initiated keratinocyte HaCaT cell cycle arrest and apoptosis, which fueled a robust secondary inflammatory response. Rats gavaged with EGFR inhibitor showed a phenotype similar to that of clinical patients, which was in line with the interrupted functions observed in HaCaT keratinocytes. We found that a nitric oxide donor, nitroglycerin, was a feasible treatment alternative for EGFR inhibitor‒induced rash. Restoration of epidermal extracellular signal‒regulated kinase and a reduction in signal transducer and activator of transcription 3 signaling through nitroglycerin treatment rescued the cellular functions that had been damaged in vitro and further ameliorated the rash in rat models. In addition, the efficacy of nitroglycerin was superior to that of existing clinical interventions. These data highlighted the importance of epidermal EGFR signaling and led to the identification of a small-molecule nitric oxide donor as a mediator that can maintain EGFR pathway functions during anti-EGFR therapies, providing a therapeutic anchor point for adverse EGFRI-induced skin effects.

Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy.

Anti-epidermal growth factor receptor (EGFR) therapy-associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.

Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma.

Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma.

An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.

SHU00238 Promotes Colorectal Cancer Cell Apoptosis Through miR-4701-3p and miR-4793-3p.

Colorectal cancer is one of the most leading causes of death. Searching for new therapeutic targets for colorectal cancer is urgently needed. SHU00238, an isoxazole derivative, was reported to suppress colorectal tumor growth through microRNAs. But the underlying mechanisms still remain unknown. Here, we explored the mechanism of SHU00238 on colorectal cancer by RT-PCR, CCK-8, flow cytometry, mirTarBase, and GO enrichment analysis. We screened partial microRNAs regulated by SHU00238 in colorectal cancer cells. Furthermore, we identified that miR-4701-3p and miR-4793-3p can reverse the acceleration of SHU00238 on colorectal cancer cell apoptosis in HCT116 Cells. Finally, we found that SMARCA5, MBD3, VPS53, EHD4 are estimated to mediate the regulation of miR-4701-3p and miR-4793-3p on colorectal cancer cell apoptosis, which targets ATP-dependent chromatin remodeling pathway and endocytic recycling pathway. Taken together, our study reveals that SHU00238 promotes colorectal cancer cell apoptosis through miR-4701-3p and miR-4793-3p, which provide a potential drug target and therapeutic strategy for colorectal cancer.