RESUMEN
Sunitinib is one of the standard targeted therapies used in metastatic renal cell carcinoma. It is generally a reasonably tolerated oral systemic therapy but can be occasionally associated with life-threatening toxicities. We present a case of reversible posterior encephalopathy, which is a rare but recognised side effect of the treatment.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Encéfalo/patología , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Pirroles/efectos adversos , Inhibidores de la Angiogénesis/administración & dosificación , Carcinoma de Células Renales/secundario , Diagnóstico Diferencial , Femenino , Cefalea/etiología , Humanos , Indoles/administración & dosificación , Neoplasias Renales/patología , Imagen por Resonancia Magnética , Persona de Mediana Edad , Síndrome de Leucoencefalopatía Posterior/complicaciones , Síndrome de Leucoencefalopatía Posterior/patología , Pirroles/administración & dosificación , Convulsiones/etiología , SunitinibRESUMEN
Oncogenic mutations in Kras 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 Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from KrasMT 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 KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, 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 KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity.