Mislocalisation of Activated Receptor Tyrosine Kinases – Challenges for Cancer Therapy

Activating mutations in genes encoding receptor tyrosine kinases (RTKs) mediate proliferation, cell migration, and cell survival, and are therefore important drivers of oncogenesis. Numerous targeted cancer therapies are directed against activated RTKs, including small compound inhibitors, and immunotherapies. It has recently been discovered that not only certain RTK fusion proteins, but also many full-length RTKs harbouring activating mutations, notably RTKs of the class III family, are to a large extent mislocalised in intracellular membranes. Active kinases in these locations cause aberrant activation of signalling pathways. Moreover, low levels of activated RTKs at the cell surface present an obstacle for immunotherapy. We outline here why understanding of the mechanisms underlying mislocalisation will help in improving existing and developing novel therapeutic strategies. Oncogenic mutations occur frequently in genes encoding RTKs. The resulting ligand-independently activated RTKs are targets for therapy in different cancer entities.Therapeutic strategies exploit RTK-directed small-molecule kinase inhibitors, antibodies, and CAR-T cells.RTK activation by oncogenic mutations frequently causes aberrant localisation in intracellular membrane systems, such as endoplasmic reticulum (ER) or Golgi. The mislocalised RTK pools signal aberrantly from intracellular membrane platforms.Therapeutic targeting of mislocalised RTKs with antibodies or CAR-T cells requires cotreatment with kinase inhibitors to promote RTK surface localisation for accessibility.Interference with intracellular RTK retention or targeting novel signalling features present novel strategies with therapeutic potential.