Downregulating neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies

Sabrina Rizzolio, Chiara Battistini, Gabriella Cagnoni, Maria Apicella, Viviana Vella, Silvia Giordano, Luca Tamagnone

Research output: Contribution to journalArticlepeer-review

Abstract

Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here, we show that the expression of Neuropi-lin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability, and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. NRP2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction.

Original languageEnglish
Pages (from-to)1058-1068
Number of pages11
JournalCancer Research
Volume78
Issue number4
DOIs
Publication statusPublished - Feb 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Downregulating neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies'. Together they form a unique fingerprint.

Cite this