Rational Targting of Oncogenic Kras and Sos Interaction in JMML
Abstract
Mutations in the KRAS gene are particularly prevalent in pediatric blood malignancies, including juvenile myelomonocytic leukemia (JMML). JMML is a rare pediatric leukemia with an estimated incidence of 1.2 cases per million children annually. JMML is characterized by over production of monocytes in peripheral blood and aggressive infiltration of these cells in multiple tissues/organs, leading to repetitive infections and organ failures. Currently, there is no effective chemotherapy to treat JMML. Bone marrow transplant is the only way to significantly prolong patient survival. Children with heterozygous somatic KRAS mutation show a particularly bad form of disease and generally have an urgent indication for transplantation. In addition, in childhood acute lymphoblastic leukemia patients who are resistant to chemotherapies, KRAS mutations are often acquired and associated with shorter survival. Our recent work attributed a large part of oncogenic KRAS function to its unique interaction with a regulator protein, called SOS1. Once we deleted SOS1 gene in leukemia cells with oncogenic KRAS, the leukemia was attenuated and the survival of these leukemia mice were prolonged. Based on this exciting discovery, we rationally designed a computer-assisted virtual screen and coupled it with experimental screen and validation. We have identified a small compound that could specifically bind to SOS1 target and interfere SOS1 binding to oncogenic KRAS protein. We used this drug lead to treat both mouse and human leukemia cells with KRAS mutations and found that it could block leukemia cell growth in the culture dish in a dose-dependent manner. In contrast, when we treated normal blood cells or leukemia cells without oncogenic KRAS, this compound did not inhibit their growth even at a very high concentration. Unlike previous Food and Drug Administration-approved drugs that target KRAS downstream proteins in both normal cells and cancer cells and thus have inherent toxicities, our compound only targets leukemia cells expressing the disease driver, oncogenic KRAS, while spares normal cells. In contrast to the recent development of KRAS inhibitors that only target one specific KRAS mutation and thus 13% of KRAS cancers, our Sos1 inhibitor approach inhibits the interaction between oncogenic Kras (regardless of oncogenic mutation residues) and Sos family members. In this application, we will further improve the potency of our compound by medicinal chemistry and test its usefulness in both mouse model and human patient leukemia cells. This study combines the complementary expertise of the leading Principal Investigator (PI) (Jing Zhang, PhD) in Ras-driven leukemia, the co-PI (Yi Zheng, PhD) in targeting RAS superfamily members with rationally designed small compounds, the co-PI (William L. Seibel, PhD) in medicinal chemistry, and the co-PIs (Eric Padron and Elliot Stieglitz, MD/PhD) in human JMML preclinical therapy studies. Structurally and biochemically, our Sos1 inhibitor approach inhibits the interaction between oncogenic Kras (beyond KrasG12D mutation) and Sos family members. The outcome of our proposed studies is to provide fundamental perspectives on targeting Sos in oncogenic KRAS-driven JMML and the underlying mechanisms. More importantly, these studies could lead to potent and efficacious novel therapies for treating the disease. In addition to hematology malignancies, oncogenic KRAS mutations are particularly prevalent in lung, pancreatic, and colon cancers. Since Sos1- mediated cross-activation of WT Ras in KrasG12D cells has also been seen in solid tumors in vivo, our study may have a broader implication to multiple oncogenic KRAS-driven cancers. We hope that the improved drug lead could be translated into the clinics in 3-5 years. Our proposed study targets the following Fiscal Year 2019 Peer Reviewed Cancer Research Program Topic Area(s): Cancer in children, adolescent, and young adults (primary) and Rare cancers (se
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010616
Entities
People
- Jing Zhang
Organizations
- United States Army
- University of Wisconsin–Madison