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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 Therapeutics

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 6

NRP1 upregulation in HER2-addicted breast carcinoma cells mediates acquired resistance to targeted therapy.

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NRP1 upregulation in HER2-addicted breast carcinoma cells mediates acqui...
(A) Immunoblotting analysis of NRP1 expression in the indicated breast cancer cells, either parental naive or with acquired resistance to the HER2-inhibitor lapatinib (Lap) (250 nM for BT474 and 120 nM for SKBR3); vinculin provided a protein loading control (1 representative experiment of at least 3 repetitions). (B) The same cells described in A were subjected to NRP1 knockdown by shRNAs (or treated with plkO empty vector); the fraction of cells resistant to lapatinib (same concentrations as indicated above) was defined as residual viability in presence of the drug versus untreated conditions (n > 4). (C) Immunoblotting analysis of IGF1R expression and tyrosine phosphorylation in lapatinib-resistant BT474 cells; vinculin provided a protein loading control (1 representative experiment of 3 repetitions). (D) IGF1R mRNA expression levels were measured by qPCR in parental or lapatinib-resistant BT474 cells, either control or upon NRP1 silencing (n = 3). Statistical significance was assessed by Student’s t test; ***P < 0.0001.
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