4 Questions for Johan Lennartsson, PhD

Johan Lennartsson, PhD

Johan Lennartsson, PhD, is an associate professor at Uppsala University and leader of the Section for Signal Transduction at the Uppsala Branch of the Ludwig Institute for Cancer Research in Uppsala, Sweden. His research focuses on platelet-derived growth factor receptor (PDGFR) and mitogen-activated protein kinase (MAPK) signaling in normal physiology and cancer. He is an expert in a wide variety of oncogenic signaling pathways, including the SCF/KIT pathway, to which he has made numerous seminal research contributions.

1

What role does SCF/KIT signaling play in normal cells?

SCF/KIT signaling most likely has different functions in different cell types. Major functions regulated by this pathway include cell survival and acting as a guiding cue for migrating cells expressing the KIT receptor. Examples of the types of cells that express KIT are primitive hematopoietic cells, germ cells, and melanocytes.

2

How important is it in cancer development, and in what kinds of cancer?

Overactivity of SCF/KIT signaling occurs through a number of different mechanisms, for example, mutational activation, SCF expression in an autocrine fashion, or receptor overexpression. In human cancer, aberrant activation of KIT has been detected in mastocytosis, gastrointestinal stromal tumors, acute myeloid leukemia, certain lymphomas, and in germ cell tumors. These tumor types reflect the normal expression pattern of KIT.

3

What are the major targeted therapies available or in development?

It has become clear that a large number of tumors have aberrant expression of receptor tyrosine kinases, and that this class of cell surface receptors frequently regulates functions such as proliferation, migration, and survival—functions that are deregulated in tumor cells. Therefore, these receptors have been used as targets for drug development, including low-molecular-weight kinase inhibitors (eg, the clinically used drug Gleevec), but other possibilities are neutralizing antibodies against the receptor (similar to the HER2-targeting antibody Herceptin) or ligand (similar to the vascular endothelial growth factor—targeting antibody Avastin). Furthermore, it is likely that these targeted therapies will be most efficient in combination with classical radio- and/or chemotherapy.

4

What is the future for this signaling pathway in cancer research?

I believe it is important to identify which signaling circuits are activated by KIT, and how these circuits contribute to the observed effects on cell survival, growth, and migration. This knowledge may then be used to develop drugs that interfere with these pathways, with the ultimate goal of simultaneously striking against both KIT receptor activity as well as intracellular circuits. This will increase the likelihood of a response and make it more difficult for resistance to evolve.

Another avenue of exploration is to identify drugs that have multiple targets, thereby inhibiting several signaling pathways essential for the cancer cell.