Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Pediatr Blood Cancer. 2019 Aug;66(8):e27790. doi: 10.1002/pbc.27790. Epub 2019 May 2.


Background: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies.

Procedure: Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells.

Results: Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK-1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K-AKT and MAPK-ERK-1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K-AKT-mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126.

Conclusions: Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.

Keywords: molecular diagnosis and therapy; pharmacology; vascular malformations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • Hemangioendothelioma / drug therapy
  • Hemangioendothelioma / metabolism
  • Hemangioendothelioma / pathology*
  • Humans
  • Infant
  • Kasabach-Merritt Syndrome / drug therapy
  • Kasabach-Merritt Syndrome / metabolism
  • Kasabach-Merritt Syndrome / pathology*
  • Lymphangioma / drug therapy
  • Lymphangioma / metabolism
  • Lymphangioma / pathology*
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Phosphatidylinositol 3-Kinases / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Retrospective Studies
  • Sarcoma, Kaposi / drug therapy
  • Sarcoma, Kaposi / metabolism
  • Sarcoma, Kaposi / pathology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases

Supplementary concepts

  • Kaposiform Hemangioendothelioma