Development of c-RAF degraders to probe KRAS mutant cancers

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.