Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model.
RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA.
During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC.
Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy.British Journal of Cancer advance online publication, 25 August 2016; doi:10.1038/bjc.2016.263 www.bjcancer.com.
British journal of cancer. 2016 Aug 25 [Epub ahead of print]
C Marcela Diaz-Montero, Frances J Mao, John Barnard, Yvonne Parker, Maryam Zamanian-Daryoush, John J Pink, James H Finke, Brian I Rini, Daniel J Lindner
Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA., Quantitative Health Sciences Department, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA., Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA., Department of Cellular and Molecular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA., Case Comprehensive Cancer Center, Case Western Reserve University Medical School, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA., Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.