Nuclear Epidermal Growth Factor Receptor is a Functional Molecular Target in Triple-Negative Breast Cancer
Menée in vitro et in vivo, cette étude suggère l'intérêt de cibler en même temps la voie de signalisation nucléaire du récepteur EGFR, par l'inhibition de son transport nucléaire, et la voie de signalisation classique EGFR, par le cétuximab, pour le traitement des cancers du sein triplement négatifs
Triple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e. estrogen receptor negative, progesterone receptor negative, and HER2 negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBC's overexpress the epidermal growth factor receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: 1) classical membrane-bound signaling, and 2) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. Based on these findings we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Further, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of TNBC patients.
http://mct.aacrjournals.org/content/early/2014/03/14/1535-7163.MCT-13-1021.abstract