Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies
Sabrina Rizzolio, … , Silvia Giordano, Luca Tamagnone
Sabrina Rizzolio, … , Silvia Giordano, Luca Tamagnone
Published August 31, 2018; First published June 28, 2018
Citation Information: J Clin Invest. 2018;128(9):3976-3990. https://doi.org/10.1172/JCI99257.
View: Text | PDF
Research Article Oncology Therapeutics

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

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

×

Figure 4

NRP1 expression confers refractoriness to targeted therapy and selective growth advantage in vivo to Met-addicted cells.

Options: View larger image (or click on image) Download as PowerPoint
NRP1 expression confers refractoriness to targeted therapy and selective...
(A and B) The viability of EBC1 (A) or GTL16 (B) Met-addicted cells, either NRP1 overexpressing or mock transfected, was assessed in the presence of increasing concentrations of the indicated Met inhibitors (n > 6). IC50 values were calculated by Graphpad. (C) NOD-SCID mice were injected subcutaneously with a heterogeneous mix of EBC1 cells, half control and half overexpressing NRP1 (n = 5, per experimental condition). In 2 complementary settings, one of the cell populations was previously marked by fluorescent Turbo-RFP, featuring a mock-RFP–labeled mix and a NRP1-RFP–labeled mix, which allowed us to follow the growth of intermingled fluorescent cells expressing different NRP1 levels by in vivo imaging with the IVIS Spectrum CT system (y axis). As expected, mouse treatment with the Met-inhibitor JNJ-605 (2.5 mg/kg by daily oral gavage) impaired the growth of control cells (revealed by fluorescent signal in mock-RFP mix tumors in this bar graph, and by gene marker–specific qPCR in Supplemental Figure 4, A and B). However, NRP1-overexpressing cells (revealed by fluorescence in NRP1-RFP mix tumors in this bar graph, and by gene marker–specific qPCR in Supplemental Figure 4B) were relatively refractory to targeted therapy. Indeed, due to overgrowth of NRP1hi cells, all tumors developed irrespective of targeted therapy (see Supplemental Figure 4, C and D). In all panels, the statistical analysis was done by 2-way ANOVA with Bonferroni’s correction, comparing the behavior of NRP1hi and mock-transfected control cells; ***P < 0.0001.