Mislocalisation of Activated Receptor Tyrosine Kinases - Challenges for Cancer Therapy

Abstract

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.

Keywords: misclocalisation; receptor tyrosine kinase; targeted therapy.