Cancer is one of the main causes of death in the Western world. It is a disease that is caused by
mutations in genes that lead to unlimited and uncontrolled proliferation and cell growth. Some of
those genes are mutated in many different cancer types, and intense research has led us to
understand the underlying mechanisms of cancer development. One of those genes is called the
Kirsten Rat Sarcoma Viral Oncogene Homolog or short KRAS, and is mutated in about a quarter of
the most aggressive cancer types including lung and pancreatic cancer. Despite intense efforts, it has
however not been feasible to develop drugs that inhibit the function of the KRAS protein or any of the
molecular processes it switches on. As a consequence, cancers that are caused by KRAS mutations
have a dismal clinical prognosis and very high mortality rates.
However, we have recently innovated a novel type of therapeutics. While traditional medicines block
malfunctioning proteins simply by binding to them, our approach earmarks unwanted proteins for the
degradation by a cellular machinery called the proteasome. Based on the design of our drugs, this
specialized cellular disposal system recognizes unwanted proteins, which consequently leads to their
rapid degradation and removal. Therefore, our approach, also called target protein degradation is
capable of completely eliminating disease-relevant proteins instead of just blocking some of their
functions.
In this project, we propose to develop novel drugs that eliminate a critical downstream effector of
mutant KRAS in lung and pancreatic cancer. This effector, called c-RAF is itself rarely mutated in
cancer, but it was shown that genetic deletion of c-RAF leads to a regression and shrinkage of KRAS-
mutant tumors in mice. We now want to test if we can similarly kill cancer cells that harbor KRAS
mutations by chemically inducing the degradation and elimination of c-RAF. Moreover, we want to
understand why KRAS mutant cancer cells are dependent on the c-RAF protein, and if we can further
augment the effect of c-RAF degraders by combining them with other cancer drugs that are either
already in the clinic, or in clinical investigation.
Through this proposal, we hope to develop and validate novel and innovative drug-candidates for the
treatment of incurable cancers, and to contribute to an improved understanding of the molecular
mechanisms of the Achilles heel of KRAS mutant cancers.