Deep sequencing reveals microRNAs predictive of antiangiogenic drug response Articles uri icon

authors

  • García Donás, Jesús
  • Esteban, Emilio
  • Castellano, Daniel E.
  • González del Alba, Aranzazu
  • Climent, Miguel Angel
  • Hernando, Susana
  • Arranz, José Angel
  • Morente, Manuel
  • Pisano, David G.
  • Robledo, Mercedes
  • Rodríguez-Antona, Cristina
  • Beuselinck, Benoit
  • INGLADA PEREZ, LUCIA
  • Graña, Osvaldo
  • Schöffski, Patrick
  • Wozniak, Agnieszka
  • Bechter, Oliver
  • Apellániz Ruiz, María
  • Leandro García, Luis Javier

publication date

  • July 2016

start page

  • 1

end page

  • 10

issue

  • 10

volume

  • 1

International Standard Serial Number (ISSN)

  • 2379-3708

abstract

  • The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twentynine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10&-9 to 3 × 10&-3). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR&-1307-3p, miR&-155-5p, and miR&-221-3p (P = 4.6 × 10&-3, 6.5 × 10&-3, and 3.4 × 10&-2, respectively). Furthermore, a 2 miRNA&-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64&-0.85; P = 1.3 × 10&-4) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10&-8 and 7.8 × 10&-7 for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment. This study was supported by the Fundación Mutua Madrileña, by an unrestricted educational grant from Pfizer (WI194736/SUT-IIG-25), by Fondo de Investigaciones Sanitarias Project PI13/0622, and by the Spanish Ministry of Economy and Competitiveness (SAF2015-70820-ERC).