Gomes Nathan, Frederick Barbara, Tentler John, Su Tin Tin
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, 80309-0347, USA.
SuviCa, Inc, PO Box 3131, Boulder, CO, 80307-3131, USA.
Sci Rep. 2025 Jul 1;15(1):21328. doi: 10.1038/s41598-025-06273-6.
Inhibitors of protein synthesis hold promise for cancer therapy because many cancer driver proteins are unstable and blocking synthesis leads to their depletion. We described previously SVC112, a small molecule inhibitor of translation elongation that inactivates Head and Neck Squamous Cell Carcinoma (HNSCC) stem cells in vitro and prevents the regrowth of HNSCC tumor xenografts in mice after radiation treatment. Here we report that SVC112 also shows activity on its own (without radiation) but with a 1600-fold range in growth inhibition among cancer cell lines of various origins. Our efforts to define molecular correlates of SVC112 sensitivity found that basal expression of apoptosis/survival factors correlates with SVC112-induced apoptosis in hematologic cancer cell lines, while phosphorylation of c-Myc correlates with sensitivity to SVC112 in colorectal cancer cell lines. Apoptosis induction by SVC112 predicts tumor growth control and survival benefit in mouse xenograft models. We suggest a paradigm wherein utility of translation inhibitors is defined by (1) inherent dependence of cancer cells on specific survival factors and (2) post-translational modifications that affect the stability of oncogenic driver proteins.
蛋白质合成抑制剂有望用于癌症治疗，因为许多癌症驱动蛋白不稳定，阻断其合成会导致它们的消耗。我们之前描述过SVC112，一种翻译延伸的小分子抑制剂，它在体外可使头颈部鳞状细胞癌（HNSCC）干细胞失活，并在放疗后防止HNSCC肿瘤异种移植瘤在小鼠体内再生长。在此我们报告，SVC112单独使用时（无放疗）也有活性，但在不同来源的癌细胞系中生长抑制范围达1600倍。我们确定SVC112敏感性分子关联的研究发现，凋亡/存活因子的基础表达与血液系统癌细胞系中SVC112诱导的凋亡相关，而c-Myc的磷酸化与结肠癌细胞系中对SVC112的敏感性相关。SVC112诱导的凋亡可预测小鼠异种移植瘤模型中的肿瘤生长控制和生存获益。我们提出一种模式，其中翻译抑制剂的效用由以下两点决定：（1）癌细胞对特定存活因子的固有依赖性；（2）影响致癌驱动蛋白稳定性的翻译后修饰。
