Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

Hui wen Lue, Daniel S. Derrick, Soumya Rao, Ahna Van Gaest, Larry Cheng, Jennifer Podolak, Samantha Lawson, Changhui Xue, Devin Garg, Ralph White, Christopher W. Ryan, Justin M. Drake, Anna Ritz, Laura M. Heiser, George V. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

Original languageEnglish (US)
Article number100267
JournalCell Reports Medicine
Volume2
Issue number5
DOIs
StatePublished - May 18 2021

Keywords

  • MEK
  • SRC
  • VEGFR
  • cabozantinib
  • cobimetinib
  • combination therapies
  • dasatinib
  • high throughput screen
  • kidney cancer
  • non-clear cell renal cell carcinoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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