JCI Insight (May 2023)

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

  • Sarah E. Sheppard,
  • Michael E. March,
  • Christoph Seiler,
  • Leticia S. Matsuoka,
  • Sophia E. Kim,
  • Charlly Kao,
  • Adam I. Rubin,
  • Mark R. Battig,
  • Nahla Khalek,
  • Erica Schindewolf,
  • Nora O’Connor,
  • Erin Pinto,
  • Jessica R.C. Priestley,
  • Victoria R. Sanders,
  • Rojeen Niazi,
  • Arupa Ganguly,
  • Cuiping Hou,
  • Diana Slater,
  • Ilona J. Frieden,
  • Thy Huynh,
  • Joseph T. Shieh,
  • Ian D. Krantz,
  • Jessenia C. Guerrero,
  • Lea F. Surrey,
  • David M. Biko,
  • Pablo Laje,
  • Leslie Castelo-Soccio,
  • Taizo A. Nakano,
  • Kristen Snyder,
  • Christopher L. Smith,
  • Dong Li,
  • Yoav Dori,
  • Hakon Hakonarson

Journal volume & issue
Vol. 8, no. 9

Abstract

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Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

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