miR-221/222 Are Involved in Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma

Abstract

Sunitinib is a multitargeting tyrosine kinase inhibitor used for metastatic renal cancer. There are no biomarkers that can predict sunitinib response. Such markers are needed to avoid administration of costly medication with side effects to patients who would not benefit from it. We compared global miRNA expression between patients with a short (≤12 months) versus prolonged (>12 months) progression-free survival (PFS) under sunitinib as first-line therapy for metastatic renal cell carcinoma. We identified a number of differentially expressed miRNAs and developed miRNA statistical models that can accurately distinguish between the two groups. We validated our models in the discovery set and an independent set of 57 patients. Target prediction and pathway analysis showed that these miRNAs are involved in vascular endothelial growth factor (VEGF), TGFβ, and mammalian target of rapamycin (mTOR)-mediated signaling and cell-cell communication. We tested the effect of these miRNAs on cellular proliferation and angiogenesis. We validated the negative correlation between miR-221 and its target, VEGFR2.miR-221 overexpression was associated with a poor PFS while its target, VEGFR2 was associated with longer survival. Gain of function experiments showed that miR-221 and miR-222 decreased angiogenesis and cellular proliferation in human umbilical vein endothelial cells (HUVEC) while increasing cellular proliferation in ACHN cells. miRNAs represent potential predictive markers for sunitinib response.

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

“…We identified 29 miRNAs predictive of TKI response and selected for validation potentially actionable miRNAs with strong effects -since only abundant miRNAs within a cell may mediate significant target suppression (21) -and miRNAs previously suggested to influence TKI response. Among the 6 miRNAs selected for validation, we obtained confirmatory results for miR-1307, which had not been previously related with RCC or TKI response, and for miR-155, miR-221, miR-425, and miR-222, for which preliminary evidence suggesting an influence on sunitinib outcome exists (17,18). Concerning miR-133a, which is suggested to regulate hypoxia (20), we found contradictory results in the discovery and validation set.…”

“…Among these 2 miRNAs, miR-NA-425 has been associated with tumor stage in gastric (32) and lung cancer (33), and in RCC, it has been suggested as being a potential ccRCC biomarker (34) associated with poor prognosis for chromophobe RCC (35) and decreased PFS during sunitinib treatment (17). miR-1307 plays a role in chemoresistance in ovarian cancer (36), and it has been suggested to contribute to colorectal carcinogenesis (37).…”

“…Its dual effect, in poor prognosis and TKI refractoriness, is supported by the key role of miR-221/222 in cell proliferation, invasion, metastasis (39), and angiogenesis (22,23). VEG-FR2 is a direct target of miR-221/222 (17), suggesting that depletion of this TKI target would render these drugs less effective. This subset of patients might therefore be more effectively treated with alternative drugs (e.g., immune checkpoint inhibitors).…”

“…This is supported by 3 exploratory studies on tumor miRNAs that, through quantitative PCR (qPCR), analyzed metastatic ccRCC cases treated with sunitinib. One study on 30 cases indicated that miR-221/222 was associated with the patients' progression-free survival (PFS) (17), another on 20 tumors proposed miR-141 as a marker for poor response to sunitinib (18), and the analysis of 6 extreme responders suggested a potential role for several miRNAs (19). However, these studies have noncoincident results and are limited by the small number of patients included and the detection of only a subset of miRNAs.…”

Novel potential predictive markers of sunitinib outcomes in long-term responders versus primary refractory patients with metastatic clear-cell renal cell carcinoma

“…The miRNA were selected on the basis of their involvement in angiogenesis, modulation of the Notch, Hedgehog and/or Wnt signaling pathways, or by being previously reported as biomarkers of Sunitinb response in renal cancer samples [23–26]. For the mRNA normalization six previously reported genes were assayed ( ACTB, TBP, GusB, GAPDH, PPIA1 and RPS13 ) and evaluated using three normalizer evaluation software (GeNorm, NormFinder and BestKeeper).…”