da Silva Fernandes Tatiane, Gillard Bryan M, Dai Tao, Martin Jeffrey C, Chaudhry Kanita A, Dugas Scott M, Fisher Alyssa A, Sharma Pia, Wu RongRong, Attwood Kristopher M, Dasgupta Subhamoy, Takabe Kazuaki, Rosario Spencer R, Bianchi-Smiraglia Anna
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, CGP L3-317, Buffalo, NY, 14263, USA.
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Sci Rep. 2025 Jan 7;15(1):1061. doi: 10.1038/s41598-024-85094-5.
Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions.
三阴性乳腺癌（TNBC）是最致命的乳腺癌亚型之一，其高复发率通常归因于对化疗的耐药性。在此，我们在多个TNBC模型中确定肌苷单磷酸脱氢酶2（IMPDH2）是导致多柔比星耐药的一个因素。对公开可用数据集的分析显示，在临床上，IMPDH2表达升高与TNBC总体预后较差相关，包括辅助/新辅助治疗后无复发生存期较短。重要的是，在多个多柔比星耐药的TNBC模型中，无论是在体外还是体内，对IMPDH2进行基因敲除和药物抑制均导致促肿瘤表型减少。总体而言，我们提出IMPDH2是一种新的易损靶点，可通过治疗手段加以利用，以抑制和/或预防化疗耐药病灶的生长。
