Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Luca Tamagnone, Silvia Giordano, Sabrina Rizzolio, Gabriella Cagnoni, Chiara Battistini, Stefano Bonelli, Claudio Isella, Jo A. Van Ginderachter, René Bernards, Federica Di Nicolantonio

Risultato della ricerca: Contributo in rivistaArticolo in rivista

27 Citazioni (Scopus)

Abstract

Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors. Notably, the combination with NRP1-interfering molecules improved the efficacy of oncogene-targeted drugs and prevented or even reversed the onset of resistance in cancer cells and tumor models. Our study provides the rationale for targeting the NRP1-dependent upregulation of tyrosine kinases, which are responsible for loss of responsiveness to oncogene-targeted therapies.
Lingua originaleEnglish
pagine (da-a)3976-3990
Numero di pagine15
RivistaTHE JOURNAL OF CLINICAL INVESTIGATION
Volume128
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Breast cancer
  • Melanoma
  • Oncology
  • Protein kinases
  • Therapeutics

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