Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

García-Donás, Jesús; Beuselinck, Benoît; Inglada-Pérez, Lucía; Graña, Osvaldo; Schöffski, Patrick; Woźniak, Agnieszka; Bechter, Oliver; Apellániz-Ruiz, María; Leandro‐García, Luis Javier; Esteban, Emilio; Castellano, Daniel; Alba, Aránzazu Gonzalez del; Climent, Miguel Ángel; Hernando, Susana; Arranz, José Ángel; Morente, Manuel M.; Pisano, David G.; Robledo, Mercedes; Rodríguez‐Antona, Cristina

doi:10.1172/jci.insight.86051

Cited by 42 publications

(37 citation statements)

References 53 publications

(60 reference statements)

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“…In ccRCC patients, expression levels of miR-221 and miR-222 significantly predicted the response to TKI therapy in two different studies [6,7]. On a functional basis, this effect was explained by miR-221 and miR-222 targeting VEGFR2 [7].…”

Section: Mir-221 As a Biomarker Candidate In Tki Therapymentioning

confidence: 99%

“…For clear-cell renal cell carcinoma (ccRCC), the tissue expression of miR-221-3p and miR-222-3p, which are two small, non-coding RNA strands originating from the same cluster, significantly predicted the response towards antiangiogenic therapies in two independent studies [6,7]. Functionally, Khella et al reasoned that this trait was associated with miR-221-3p/miR-222-3p specifically binding the mRNA of KDR/VEGFR2, which decreases VEGFR2 protein levels [7].…”

Section: Introductionmentioning

confidence: 99%

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miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

Krebs

Solimando

Kalogirou

et al. 2020

JCM

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Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.

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Section: Mir-221 As a Biomarker Candidate In Tki Therapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

Krebs

Solimando

Kalogirou

et al. 2020

JCM

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“…The severity of pazopanib-induced hand-foot skin reaction was also correlated to AUC of pazopanib [30]. Therefore been suggested that rs776746 in the CYP3A5 gene can be a dose reduction marker of sunitinib, because rs776746 A allele carriers have higher concentrations of sunitinib [56]. Furthermore, carriers of the ABCG2 rs2231142 AA genotype have higher AUC of substrate drugs than carriers of the CC genotype [57,58].…”

Section: Tki-induced Hand-foot Skin Reactionmentioning

confidence: 99%

Genetic polymorphisms associated with adverse reactions of molecular-targeted therapies in renal cell carcinoma

Yamamoto

Yano

2018

Med Oncol

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The prognosis of patients with metastatic renal cell carcinoma has drastically improved due to the development of molecular-targeted drugs and their use in clinical practice. However, these drugs cause some diverse adverse reactions in patients and sometimes affect clinical outcomes of cancer therapy. Therefore, predictive markers are necessary to avoid severe adverse reactions, to establish novel and effective prevention methods, and to improve treatment outcomes. Some genetic factors involved in these adverse reactions have been reported; however, perspectives on each adverse response have not been integrated yet. In this review, genetic polymorphisms relating to molecular-targeted therapy-induced adverse reactions in patients with renal cell carcinoma are summarized in the points of pharmacokinetic and pharmacodynamic mechanisms. We also discuss about the relationship between systemic drug exposure and adverse drug reactions.

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“…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).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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BackgroundSeveral potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation.Patients and methodsMulticenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS.Results123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found.ConclusionsCertain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response.

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Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

Cited by 42 publications

References 53 publications

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

Genetic polymorphisms associated with adverse reactions of molecular-targeted therapies in renal cell carcinoma

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

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