Cellular Oncology最新文献

Purpose: Cholesterol dysregulation plays a central role in tumor progression and has emerged as a potential therapeutic target. Its dysregulation within the tumor microenvironment is increasingly considered a strong modifier of multiple cancer traits. Targeting cholesterol, particularly its biosynthetic pathway, has been explored to enhance therapy, yet outcomes remain inconsistent, likely reflecting a tumor-specific reprogramming of cholesterol metabolism.

Methods: TCGA and GTEx transcriptomic data from 11,735 samples was analyzed to conduct an integrative assessment of key cholesterol-related processes-biosynthesis, uptake, storage, efflux, and catabolism-across 26 cancer types.

Results: Cholesterol metabolism dysregulation was highly heterogeneous among tumors, affecting different metabolic pathways, the magnitude of those differences and the direction relative to normal tissue. Notably, we identified cholesterol uptake as the most consistently altered pathway across tumors, positively correlated with tumor aggressiveness and poorer patient survival. Uptake correlated positively with inflammatory pathways (e.g., Complement System and IL-6-JAK-STAT3 Signaling) and with immune microenvironment features, including Tregs, cytotoxic and CD4⁺ T cells, eosinophils, endothelial cells, as well as elevated expression of immune checkpoints. Cholesterol uptake also correlated with enhanced KRAS signaling. Particularly, KRAS mutations were more frequent in tumors with high uptake scores, and those patients had the worst overall survival. Nonetheless, high uptake tumors lacking KRAS mutations had higher KRAS signaling scores than KRAS-mutant tumors with low uptake, highlighting a central role of cholesterol uptake on the regulation of KRAS signaling.

Conclusion: In summary, cholesterol uptake emerges as a conserved driver of tumor aggressiveness and a promising therapeutic target to synergize with immunotherapy and KRAS inhibition.

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.