Data from Oncogenic <i>Kras</i> Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17

Abstract

<div>Abstract<p>Oncogenic mutations in <i>Kras</i> occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant <i>Kras</i> in regulating growth factor shedding and ADAM17 activity, using isogenic <i>Kras</i> mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from <i>Kras</i>MT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-α shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in <i>Kras</i>MT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding <i>in vivo</i>, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in <i>Kras</i>MT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent <i>in vitro</i> and <i>in vivo</i>. Collectively, our findings indicate that oncogenic <i>Kras</i> regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that <i>Kras</i>MT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity. <i>Cancer Res; 71(3); 1071–80. ©2010 AACR</i>.</p></div>