GSE171358
Identification of clinical combination therapies to induce durable responses in kidney cancers
The lack of effective treatment optionsfor 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, weidentified the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acted synergistically in cells to markedly reduce cell viability. Importantly, the combination was well tolerated and caused tumor regression in vivo. Transcriptional and phosphoproteomic profilingrevealed that the combination converged to downregulate the MAPK-ERK signaling pathway, a result not predicted by single agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergized with either dasatinib or cabozantinibto increase its efficacy. This study, by employing approved, clinically relevant drugs provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic. Overall design: Gene expression profiles of triplicate ACHN cells treated for 24 hours with dasatinib, cabozantinib, and dasatinib + cabozantinib co-treatment.