Fresh Ways of Targeting KRAS Emerge in Signaling Networks

Barry D. Nelkin, PhD, shown in his laboratory at Johns Hopkins, explores the molecular mechanisms of several types of cancer.

1. Please describe your research interests as they relate to KRAS.

2. What makes KRAS such an important target for cancer therapy?

3. What is currently the most promising strategy for targeting KRAS?

4. What is the most exciting recent finding relating to the development of novel KRAS-targeting strategies?

Barry D. Nelkin, PhD, focuses on understanding the molecular mechanisms of thyroid, pancreatic, and prostate cancers, and developing novel therapies for these diseases. Nelkin, a professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, has focused on the Ras/Raf/MEK pathway. With the aid of funding from the Patrick C. Walsh Prostate Cancer Research Fund, the National Cancer Institute, and other sources, his lab has identified and is further investigating a promising new target in a KRAS-related pathway, cyclin-dependent kinase 5 (CDK5).We have been interested in the RAS family of genes for many years. Currently, we are very excited about the therapeutic potential to block the main downstream effector pathways of KRAS: the Raf/MEK/ERK, PI3K/Akt, and Ral pathways. Our recent focus has been on the Ral pathway in pancreatic cancer, since pancreatic cancers almost always have an activating mutation in KRAS. Ral is central to KRAS effects in pancreatic cancer, and we have recently discovered a druggable target, CDK5, in the Ral pathway in pancreatic cancer.KRAS, and less commonly other RAS family members, is mutated in approximately 30% of cases of human cancer, and Ras signaling is aberrantly activated in many or most cancer cases—even those without RAS mutations. KRAS is mutated in over 90% of the cases of pancreatic cancer. This strongly suggests that KRAS is necessary for tumorigenesis in many instances, and that its inhibition would be therapeutically effective. This suggestion is strongly supported by many preclinical studies.The most promising strategies currently in clinical trials target downstream effector pathways of KRAS. In general, combination targeting of the Raf/MEK/ERK and PI3K/Akt effector pathways has been required for effective inhibition of KRAS-dependent tumor growth, as had been predicted from preclinical studies. Nevertheless, a major effector pathway, Ral, has not been targetable until now, and this pathway may provide a resistance mechanism, limiting efficacy of combination targeted therapy. As mentioned, we have recently identified a way to target Ral in pancreatic cancer; it appears to be effective in combination in preclinical models, and we have recently initiated a combination therapy clinical trial to explore this strategy in pancreatic cancer.Perhaps the most exciting recent findings relate to direct targeting of KRAS. Years ago, the entire RAS field was excited by the potential of farnesyl transferase inhibitors to target Ras directly, and we were terribly disappointed that they did not fulfill their promise, due to limited specificity and to innate resistance mechanisms. It has been frustrating that although we have recognized the importance of Ras proteins in cancer for 30 years, we had not been able to find therapeutic compounds that bind to Ras until recently.

Within the past two years, at least five groups (G. Fang, Genentech; S. Fesik, Vanderbilt; N. Gray, Harvard; F. McCormick, UCSF; K. Shokat, UCSF) have reported small molecules that bind to KRAS, renewing our optimism that KRAS can be targeted directly. In addition, one group has reported a novel strategy for sequestering Ras proteins in an inactive form by preventing its interaction with the prenyl-binding protein PDEδ.

5. What are the most significant barriers to the development of effective KRAS-targeting agents?

These are exciting times for RAS research. Based on these and other results, the National Cancer Institute has launched a national RAS research initiative, led by Frank McCormick, PhD, and based at Frederick National Laboratory, to accelerate our ability to target RAS therapeutically.After 30 years, we are still early in development of KRAS-targeted therapeutics, and the barriers are still unknown. I speculate that the most significant hurdles will be those we have seen in similar targeted therapies—toxicity, and innate and acquired resistance. We have already seen significant toxicity in combination therapies targeted toward the Raf/MEK/ERK and PI3K/Akt pathways. One can readily imagine resistance due to alternative mechanisms of activation of KRAS-driven effector pathways. Nevertheless, these potential challenges will be addressed, and cannot dampen our enthusiasm.