Aberrant function and regulation of small GTPases is often associated with the development of human malignancies, thus rendering these proteins highly interesting targets in drug discovery. Several bacterial toxins are known to irreversibly inactivate small GTPase signaling to effectively block host immune response and enable survival of the bacterium within the hostile environment, but their exploitation as therapeutics against cancer has yet to be realized. Recently, we found that RRSP, an effector domain of bacterial MARTX toxins, specifically cleaves the common oncogenic Ras and thereby kills cancer cells. Ras is small a GTPase that centrally regulates cell growth. Ras mutations often drive constitutive cell proliferation and are found in 30% of cancers, including lung, colorectal, and pancreatic cancers. In particular, specific mutations in KRas isoforms are directly involved in the initiation and progression of 90% of human pancreatic cancers. Ras has been deemed as “undruggable”, since three decade of effort did not yield clinically relevant direct inhibitors. Moreover, targeting Ras downstream effectors has failed as a therapeutic strategy due to acquired resistance of cancer cells. Thus, for drug development against Ras, radically novel approaches are urgently needed. We hypothesize this RRSP enzymatic function and/or its effects on Ras structure can be harnessed for novel cancer treatments. Here we propose to investigate first the structure of KRas-RRSP complex to identify the aminoacid resides involved in the interactions. Second we will be using pancreatic cell lines harboring oncogenic KRas G12V and G12D to elucidate RRSP activity into these cells. Third, we will study the effect on the Ras Switch I cleavage by RRSP, on the localization, mobility and dynamics of KRas molecules on the plasma membrane. The planned research promises to reveal new structure and in vivo function information of KRas inhibition by RRSP, which might be exploited for drug development. Further, knowledge of the mechanism of RRSP processing and inhibition of KRas could facilitate development of RRSP or RRSP mimics as novel therapeutics for pancreatic cancer patients. This project matches with the RAS Initiative of NCI to attract cutting-edge ideas to the Pancreatic Cancer Action Network. This proposed project will continue the innovative and productive research currently funded by PanCan through a 2016 one-year KRas fellowship. During the first half of my 2016 fellowship, the research has benefited enormously from expertise and collaborations with the Ras Initiative, an intended advantage of this program. With extended funding, I would be able to continue developing this project in collaboration with FNLCR and propel the research to a higher degree of impact. Over the long-term, this project will reveal new insight of oncogenic KRas structure and function and greatly impact cancer therapy research and development.
|Effective start/end date||7/1/17 → 9/30/17|
- Pancreatic Cancer Action Network, Inc. (17-40-BIAN//HHSN26120080001E)
- National Cancer Institute (17-40-BIAN//HHSN26120080001E)