Cellular Oncology最新文献

Purpose: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as the standard-of-care first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, EGFR-TKI resistance has become a major challenge for almost all patients with EGFR-mutated NSCLC. Both amivantamab (EGFR-MET bispecific antibody) and patritumab deruxtecan (HER3 antibody-drug conjugate) have shown promising efficacy in clinical trials for NSCLC resistant to osimertinib. This study aimed to evaluate a novel therapeutic strategy combining amivantamab and patritumab deruxtecan to overcome osimertinib resistance in NSCLC.

Methods: Three osimertinib-resistant non-small cell lung cancer cell lines were established in vitro. Changes in relevant targets between pre- and post-resistance states were explored at the RNA and protein levels. Subsequently, the efficacy and safety of combination therapy were verified in vitro and in vivo respectively. Changes in treated mice immune microenvironment post-combination therapy were analyzed by flow cytometry, while bulk-RNA sequencing was conducted on tumor tissues.

Results: We found that in vitro studies, when combined, amivantamab and patritumab deruxtecan both exhibited a synergistic effect on cell lines that were sensitive or resistant to Osimertinib, and the use of amivantamab increases the expression of HER3 in certain cell lines. Furthermore, the combination therapy polarized macrophages toward the M1 phenotype in vivo, thereby constructing an immune microenvironment unfavorable for tumor growth.

Conclusion: In conclusion, we have proposed a new therapeutic strategy for NSCLC after osimertinib resistance. The combined strategy of amivantamab and patritumab deruxtecan highlight a promising therapeutic avenue, warranting future clinical trials to validate safety and efficacy.

Background: Pancreatic cancer is typically accompanied by fibrosis, forming a dense stromal matrix. This dense matrix restricts drug penetration, making it difficult for drugs to effectively reach tumor cells. Additionally, pancreatic cancer has inadequate local blood supply and "vascular irregularity," which makes it challenging for drugs to reach the core of the tumor. Even if some drugs reach the pancreas through systemic circulation, poor vascular permeability prevents them from effectively entering tumor cells, resulting in suboptimal therapeutic effects. Statins were initially used to treat high cholesterol levels and prevent cardiovascular diseases, but recent studies suggest that they may also have potential therapeutic effects on cancer, particularly certain types of cancer such as pancreatic cancer. However, clinical research on the use of statins for pancreatic cancer treatment is still ongoing, and the results are inconsistent. The effects of statins on pancreatic cancer may vary depending on the dose. Due to the aforementioned limitations of fibrosis and lack of blood supply in pancreatic cancer, simvastatin only exerts its effect on pancreatic cancer cells at low doses.

Purpose: This study aimed to explore the effects of low-dose simvastatin on pancreatic cancer cells and the underlying mechanisms. We investigated the effects of different concentrations of simvastatin on pancreatic cancer cells.

Methods: The vitality of the cells was evaluated by CCK8, EDU staining, and the level of ferroptosis in pancreatic cancer cells was detected by flow cytometry detection of C11, MDA, ROS.

Results: We found that small doses of simvastatin can resist the toxicity of Erastin against pancreatic cancer cells. Under the transmission electron microscope, more mitophagosomes were produced in pancreatic cancer cells treated with small dose of simvastatin, and immunofluorescence revealed increased co-localization of lysosomes and mitochondria, indicating that simvastatin promoted the occurrence of mitophagy. At the same time, immunofluorescence confirmed that simvastatin promoted the nuclear translocation of TFEB, and chromatin immunoprecipitation and dual-luciferase gene report confirmed that TFEB is the transcription factor of P62/SQSTM1. This study clarified that a small dose of simvastatin, in the event of mitochondrial stress in pancreatic cancer cells, induces mitophagy to clear damaged mitochondria, protecting pancreatic cancer cells from ferroptosis and apoptosis, by promoting the transcription of P62/SQSTM1 through the nuclear translocation of TFEB.

Conclusion: These findings may explain one of the reasons for the suboptimal efficacy of simvastatin in the treatment of pancreatic cancer, while also providing new insights for research on the antitumor effects of statins.

Purpose: CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9's involvement in transcriptional addiction in cancer. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.

Methods: We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models.

Results: Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-β and Wnt/β-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity.

Conclusion: Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.