Clear Cell Renal Cell Carcinomas That Respond to Tyrosine Kinase Inhibitor Sunitinib Have Distinct microRNA Expression Patterns from Non-Responders
Ming Zhou, Karen Streator Smith, Paula Carver, Sara Falzarano, Laura Wood, Brian Rini, Cristina Magi-Galluzzi. Cleveland Clinic, Cleveland, OH; New York Univeristy, New York
Background: The tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for metastatic clear cell renal cell carcinoma (mCCRCC). However, lack of therapeutic benefit and significant toxicity are seen in a significant proportion of patients receiving the treatment. Therefore, identification of biomarkers that predict clinical benefit is critical. Recent studies have shown that microRNAs (miRNAs) play critical roles in the development and metastasis of human cancers. We aimed to study whether miRNA expression patterns may predict response to sunitinib in patients with mCCRCC.
Design: Twenty-three patients with mCCRCC were treated with sunitinib and categorized as “responders” (duration of disease control on sunitinib > 12 months) and “non-responders” (lack of any disease control on sunitinib). Whole cell RNA was extracted from formalin-fixed paraffin-embedded (FFPE) pre-treatment nephrectomy specimens. Using high-throughput real-time PCR-based miRNA microarrays, the expression profiles of 768 miRNAs were compared in these two groups.
Results: The expression levels of 12 (1.6%) miRNAs were significantly different between the responders and non-responders (p<0.05). The fold change was greater than 2 for 7 miRNAs. MiRNAs miR-187, miR-191*, miR-302c, miR-632, miR-19a* and miR-1257 were significantly overexpressed in sunitinib responders compared with non-responders and the fold change was 2.1, 2.3, 1.9, 1.9, 1.5 and 1.8, respectively (p values all <0.05). MiRNAs miR-9, miR-138, miR-9*, miR-376a*, miR-144* and miR-223* were significantly down-regulated in sunitinib responders, and the fold change was 0.20, 0.23, 0.21, 0.53, 0.49 and 0.44, respectively (p values all <0.036).
Conclusions: By whole genome miRNA screening, 12 miRNAs were found to have differential expression patterns between CCRCC that responded to sunitinib treatment and non-responders. Several of these miRNAs were reported in the literature to affect the maturation of immune regulatory bone marrow derived dendritic cells (miR-223) and hypoxia inducible pathways (miR-138). These findings suggest that miRNAs could be informative biomarkers for predicting response to tyrosine kinase inhibitors in patients with mCCRCC.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 11:15 AM
Platform Session: Section A, Tuesday Morning