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Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies
Sabrina Rizzolio, … , Silvia Giordano, Luca Tamagnone
Sabrina Rizzolio, … , Silvia Giordano, Luca Tamagnone
Published June 28, 2018
Citation Information: J Clin Invest. 2018;128(9):3976-3990. https://doi.org/10.1172/JCI99257.
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Research Article Oncology Article has an altmetric score of 11

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

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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.

Authors

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

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Figure 2

miRNA-338 downregulation mediates NRP1 neoexpression in BRAF inhibitor–resistant melanoma cells.

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miRNA-338 downregulation mediates NRP1 neoexpression in BRAF inhibitor–r...
(A) The expression of miRNA-338-3p was assessed by quantitative real-time PCR in PLX-4720–resistant A375 and SK-MEL-28 melanoma cells, and normalized versus the respective parental cells (n = 5). Student’s t test, ***P < 0.0001. (B) qPCR analysis of NRP1 (left graph) and EGFR (right graph) expression in drug-resistant A375 and SK-MEL-28 cells, transfected in order to reexpress miR-338 (values normalized to respective mock-transfected cells) (n = 4). (C) NRP1 expression assessed by immunoblotting in parental and PLX-4720–resistant A375 cells transfected with pre–miRNA-338 (or mock transfected); vinculin provided a protein loading control (1 representative experiment of 5 repetitions). (D) Viability of drug-resistant (or parental) A375 and SK-MEL-28 cells, transfected with miR-338 or mock (as shown in B; values normalized to respective mock-transfected cells) (n = 3).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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