Mughees Mohd, Tacam Moises J, Tan Alex W, Pitner Mary K, Iles LaKesla R, Hu Xiaoding, S Villodre Emilly, Debeb Bisrat G, Kogawa Takahiro, Lim Bora, Layman Rachel M, Woodward Wendy A, Ueno Naoto T, Tripathy Debu, Krishnamurthy Savitri, Qi Yuan, Pusztai Lajos, Wang Jian, Gandhi Varsha, Bartholomeusz Geoffrey, Bartholomeusz Chandra
The University of Texas MD Anderson Cancer Center, Houston, United States.
The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Mol Cancer Ther. 2025 May 13. doi: 10.1158/1535-7163.MCT-24-0593.
The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic-lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and SUM149-R (triple-negative inflammatory breast cancer). These resistant cells were characterized with respect to different parameters, and a combination of an MCL-1 inhibitor (MCL-1i) together with a MEKi was evaluated in vitro and in vivo to overcome the acquired resistance. Compared with their respective parental cells, MDA-MB-231-R and SUM149-R cells showed increased proliferation, colony formation, stemness, anchorage-independent growth, and MCL-1 expression levels. MCL-1 knockdown in resistant cells decreased cell proliferation and colony formation, increased apoptosis, and was associated with high expression of the pro-apoptotic proteins PUMA, NOXA, BAK, and BAX. MEKi resistance was overcome when resistant cells were treated with MCL-1i and MEKi combined. In an in vivo mouse model, inhibition of MCL-1 restored sensitivity to AZD6244. Our results suggest that MCL-1 is a driver of MEKi resistance and that combining an MCL-1i with a MEKi warrants further investigation in triple-negative and triple-negative inflammatory breast cancer.
丝裂原活化蛋白激酶（MAPK）信号通路可导致侵袭性很强的乳腺癌产生耐药性。我们之前的研究表明，MEK抑制剂（MEKi）AZD6244（司美替尼）可预防乳腺癌异种移植模型中的肺转移。在临床研究中，由于耐药性的出现，MEKi作为单一药物对实体瘤的活性仅为中等。通过合成致死性siRNA筛选，我们确定髓样细胞白血病-1（MCL-1）是导致AZD6244耐药的一个潜在因素。我们推测，MCL-1在侵袭性很强的乳腺癌中促进了对MEKi的耐药性，而抑制MCL-1可克服AZD6244耐药性。我们建立了两种对AZD6244耐药的细胞系：MDA-MB-231-R（三阴性乳腺癌）和SUM149-R（三阴性炎性乳腺癌）。对这些耐药细胞的不同参数进行了表征，并在体外和体内评估了MCL-1抑制剂（MCL-1i）与MEKi联合使用以克服获得性耐药的效果。与各自的亲本细胞相比，MDA-MB-231-R和SUM149-R细胞表现出增殖增加、集落形成增加、干性增强、不依赖贴壁生长以及MCL-1表达水平升高。耐药细胞中MCL-1的敲低降低了细胞增殖和集落形成，增加了细胞凋亡，并且与促凋亡蛋白PUMA、NOXA、BAK和BAX的高表达相关。当耐药细胞用MCL-1i和MEKi联合处理时，对MEKi的耐药性被克服。在体内小鼠模型中，抑制MCL-1恢复了对AZD6244的敏感性。我们的结果表明，MCL-1是MEKi耐药的驱动因素，并且将MCL-1i与MEKi联合使用在三阴性和三阴性炎性乳腺癌中值得进一步研究。
