Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies
Sabrina Rizzolio, Gabriella Cagnoni, Chiara Battistini, Stefano Bonelli, Claudio Isella, Jo A. Van Ginderachter, René Bernards, Federica Di Nicolantonio, Silvia Giordano, Luca Tamagnone
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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Research Article Oncology

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

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Figure 9

Therapeutic efficacy of NRP1-interfering molecules in combination with BRAF-, HER2-, or Met-targeted inhibitors.

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Therapeutic efficacy of NRP1-interfering molecules in combination with B...
(A) The viability of EBC1 Met-addicted cells (n = 5) was assessed upon treatment with increasing concentrations of the Met inhibitor JNJ-605, either alone or in combination with the NRP1-targeted molecule EG00229 (12.5 μM) or the nanobody HS45 (5 μg/ml). (B) HER2-addicted BT474 breast cancer cells, either parental naive or resistant to the targeted inhibitor lapatinib (250 nM), were exposed to lapatinib alone or in combination with EG00229 (12.5 μM); the fraction of drug-resistant cells was calculated based on residual viability versus untreated conditions (n = 4). (C) EGFR mRNA levels were measured in SOX10-depleted A375 melanoma cells (or controls) (n = 4), treated with the NRP1-targeted molecule EG00229 (12.5 μM) or with vehicle alone. (D) Viability of SOX10-depleted A375 melanoma cells (or controls) (n > 4) exposed to 0.25 μM PLX-4720, either alone or in combination with the small molecule EG00229 (12.5 μM) or HS45 nanobody (5 μg/ml). (E) The growth of A375 melanoma cells, parental or PLX-4720 resistant (n = 3), was assessed after 2 weeks of culture in the presence of the BRAF inhibitor PLX-4720, either alone or in combination with 12.5 μM EG00229 (representative images at the bottom). (F) Residual viability of BRAF inhibitor–resistant A375 melanoma cells subjected to different therapeutic associations of PLX-4720 (2 μM) with cetuximab (1 μg/ml) and/or EG00229 (12.5 μM); the statistical analysis compared combinatorial treatments with PLX-4720 alone (n = 5). We applied ANOVA tests with Bonferroni’s correction to analyze multiple sample comparisons in A, D, F; in the other cases, we used Bonferroni-corrected Student’s t tests; *P < 0.01, **P < 0.001, ***P < 0.0001.