Biondini Marco, Kiepas Alex, El-Houjeiri Leeanna, Annis Matthew G, Hsu Brian E, Fortier Anne-Marie, Morin Geneviève, Martina José A, Sirois Isabelle, Aguilar-Mahecha Adriana, Gruosso Tina, McGuirk Shawn, Rose April A N, Tokat Unal M, Johnson Radia M, Sahin Ozgur, Bareke Eric, St-Pierre Julie, Park Morag, Basik Mark, Majewski Jacek, Puertollano Rosa, Pause Arnim, Huang Sidong, Keler Tibor, Siegel Peter M
Goodman Cancer Research Institute, McGill University, Montreal, QC, Canada.
Department of Medicine, McGill University, Montreal, QC, Canada.
Oncogene. 2022 Mar;41(12):1701-1717. doi: 10.1038/s41388-022-02206-z. Epub 2022 Feb 2.
Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.
跨膜糖蛋白NMB（GPNMB）是三阴性乳腺癌（TNBC）患者预后不良的一个预后标志物。Glembatumumab Vedotin是一种靶向GPNMB的抗体药物偶联物，作为单一药物，它对GPNMB阳性转移性TNBC的疗效存在差异。我们发现，针对多种乳腺癌亚型的标准治疗和实验性治疗会使GPNMB水平升高。虽然这些治疗应激源通过转录因子MiTF家族的不同参与来诱导GPNMB表达，但并非所有应激源都能增加Glembatumumab Vedotin抑制所需的GPNMB细胞表面定位。通过基于荧光激活细胞分选（FACS）的基因筛选，我们发现抑制热休克蛋白90（HSP90）会同时增加GPNMB表达和细胞表面定位。从机制上讲，HSP90抑制导致溶酶体向细胞周边分散并与质膜融合，从而将GPNMB递送至细胞表面。最后，在体内用HSP90抑制剂治疗可使乳腺癌对Glembatumumab Vedotin敏感，这表明HSP90抑制剂与Glembatumumab Vedotin联合使用可能是转移性TNBC患者一种可行的治疗策略。
