Targeting Ras and Rho Family GTPases for the Treatment of Cancer Through Inhibition of CAAX-Signaled Modifications and the ERK MAPK Pathway. Public Deposited

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  • March 20, 2019
Creator
  • Roberts, Patrick
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
Abstract
  • Ras and Rho family GTPases share many structural and biochemical similarities while regulating distinct cellular functions. One such similarity is the carboxyl-terminal CAAX motif (C = cysteine, A = aliphatic amino acid, and X = terminal amino acid), which signals a series of post-translational modifications important for proper subcellular localization. These modifications are catalyzed by prenyltransferase enzymes, farnesyltransferase (FTase) or geranylgeranyltransferase I (GGTase-I), and subsequently by the endoprotease Ras converting enzyme 1 (Rce1) and by isoprenylcysteine-O-carboxyl methyltransferase (Icmt). Fully processed proteins are thus prenylated, clipped and methylated. Prenylation is known to be absolutely required for correct subcellular localization and biological function of small GTPases. The importance of the post-prenyl processing steps has not been as well validated. The overwhelming evidence that aberrant Ras signaling is critical in oncogenesis, and emerging data supporting similar importance for Rho, has resulted in intense efforts to develop inhibitors of these proteins. Two main approaches are currently underway. The first approach exploits the requirement for CAAX processing, resulting in the development of FTase and GGTase inhibitors now in the clinic. The second approach is to block downstream effector pathways, such as the MAPK pathways. We evaluated these two approaches in Ras-mutant non-small cell lung cancer (NSCLC). Efforts to develop anti-Ras therapies have revealed great complexity in Ras effector utilization, and some therapies (FTase inhibitors, FTIs) have been met with unexpected resistance. Therefore, we examined the requirement for downstream ERK MAPK signaling in Ras-mutant NSCLC and determined that this pathway is critical for Ras-mutant NSCLC. In addition, using genetic and pharmacologic approaches we validated that Icmt methylation is also required, further supporting it as a novel target for drug development. While FTIs do not block Ras, they have shown some success in clinical trials, yet their mechanism is unknown. We have identified several Rho proteins as potential targets of FTase inhibition, which should aid in the future development of these compounds. Finally, we show here that Rho family localization is also exquisitely dependent on Rce1 and Icmt, indicating that Rce1 and Icmt are promising targets to block aberrant Rho signaling in cancer.
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  • In Copyright
Advisor
  • McLeod, Howard L.
  • Der, Channing
  • Cox, Adrienne
  • Hawke, Roy
  • Brouwer, Kim L. R.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2008
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