Abstract B014: GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma

Abstract GPNMB (Glycoprotein non-metastatic melanoma protein B) is a canonical transcriptional target of MiT/TFE proteins (TFEB/TFE3/MITF), expressed at low levels in normal tissues but upregulated in numerous MiT/TFE-driven tumors such as translocation RCC, alveolar soft part sarcoma and MITF-driven melanoma, where it is associated with poor prognosis. CDX-011 (CR011-MMAE) is an anti-GPNMB ADC, with demonstrated efficacy in pre-clinical models of TFE3-fusion RCC. To further characterize GPNMB functionality and value as a cell-surface therapeutic target in tRCC, we engineered cell lines with genomic deletion of GPNMB via CRSIPR-Cas9 editing. Deletion of GPNMB in PRCC-TFE3 cell lines [UOK120/UOK124] significantly decreased clonogenic growth in 2D, spheroid size and viability and tumor xenograft growth in NSG mice and was associated with a decrease in phosphorylation of mTORC1 substrates [p-P70S6K, p-4EBP1]. We then examined expression of CD44, the primary receptor for GPNMB, and a tumor-associated antigen associated with poor prognosis in many cancers. Expression of CD44 and its ligand SPP1/OPN, was significantly increased in bulk RNA-Seq data from multiple transgenic models of SFPQ-TFE3, PRCC-TFE3 and ASPSCR1-TFE3, in human tRCC cases compared to normal kidney, and in SFPQ-TFE3/ PRCC-TFE3 transgenic kidney tumors and an ASPSCR-TFE3 PDX model, by immunoblotting and IHC, with increased membrane localization. shRNA-mediated depletion of CD44 profoundly and specifically decreased clonogenicity of multiple TFE3-fusion lines, with no effect seen in ccRCC lines. In conclusion, GPNMB regulates the growth of tRCC cells, potentially via an autocrine mechanism involving its receptor CD44, and targeting GPNMB-CD44 signaling may be of therapeutic benefit in tRCC. Citation Format: Kaushal Asrani, Juhyung Woo, Kewen Feng, Thiago Vidotto, Adrianna Amaral, Vikrant Palande, Jayaprakash Mandal, Eddie Imada, Christopher Thoburn, Sangeeta Ray, Huili Li, Yasser Ged, Nirmish Singla, John A. Copland, Laura Schmidt, W. Marston Linehan, Pedram Argani, Tamara Lotan. GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B014.