Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma

Yige Wu, Siqi Chen, Xiaolu Yang, Kazuhito Sato, Preet Lal, Yuefan Wang, Andrew T. Shinkle, Michael C. Wendl, Tina M. Primeau, Yanyan Zhao, Alanna Gould, Hua Sun, Jacqueline L. Mudd, Jeremy Hoog, R. Jay Mashl, Matthew A. Wyczalkowski, Chia Kuei Mo, Ruiyang Liu, John M. Herndon, Sherri R. DaviesDi Liu, Xi Ding, Yvonne A. Evrard, Bryan E. Welm, David Lum, Mei Yee Koh, Alana L. Welm, Jeffrey H. Chuang, Jeffrey A. Moscow, Funda Meric-Bernstam, Ramaswamy Govindan, Shunqiang Li, James Hsieh, Ryan C. Fields, Kian Huat Lim, Cynthia X. Ma, Hui Zhang, Li Ding, Feng Chen

Research output: Contribution to journalArticlepeer-review


Current treatment approaches for renal cell carcinoma (RCC) further identified a tumor subpopulation enriched with cell-cycle face challenges in achieving durable tumor responses due to tumor activity that exhibited heightened sensitivity to the cabozantinib heterogeneity and drug resistance. Combination therapies that and sapanisertib combination. Conversely, activation of the epileverage tumor molecular profiles could offer an avenue for thelial–mesenchymal transition pathway, detected at the protein enhancing treatment efficacy and addressing the limitations of level, was associated with drug resistance in residual tumors current therapies. To identify effective strategies for treating RCC, following combination treatment. The combination effectively we selected ten drugs guided by tumor biology to test in six RCC restrained ERK phosphorylation and reduced expression of ERK patient-derived xenograft (PDX) models. The multitargeted tyro-downstream transcription factors and their target genes implicated sine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor in cell-cycle control and apoptosis. This study highlights the sapanisertib emerged as the most effective drugs, particularly when potential of the cabozantinib plus sapanisertib combination as a combined. The combination demonstrated favorable tolerability promising treatment approach for patients with RCC, particularly and inhibited tumor growth or induced tumor regression in all those whose tumors progressed on immune checkpoint inhibitors models, including two from patients who experienced treatment and other TKIs. failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed Significance: The molecular-guided therapeutic strategy of coma significant reduction in vascular density, and single-nucleus bining cabozantinib and sapanisertib restrains ERK activity to RNA sequencing (snRNA-seq) analysis indicated a decreased effectively suppress growth of renal cell carcinomas, including those proportion of endothelial cells in the tumors. SnRNA-seq data unresponsive to immune checkpoint inhibitors.

Original languageEnglish
Pages (from-to)4161-4178
Number of pages18
JournalCancer research
Issue number24
StatePublished - Dec 15 2023


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