TY - JOUR
T1 - Downregulating neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies
AU - Rizzolio, Sabrina
AU - Battistini, Chiara
AU - Cagnoni, Gabriella
AU - Apicella, Maria
AU - Vella, Viviana
AU - Giordano, Silvia
AU - Tamagnone, Luca
PY - 2018/2/15
Y1 - 2018/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-2020
DO - 10.1158/0008-5472.CAN-17-2020
M3 - Article
C2 - 29229599
AN - SCOPUS:85042174008
VL - 78
SP - 1058
EP - 1068
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 4
ER -