THESIS DEFENSE — PUBLIC SEMINAR: Elucidating the function of isoprenylcysteine carboxylmethyltransferase (Icmt) in cancer

Start Date & Time: 
Tuesday, 20 June, 2017 - 10:00
End Date & Time: 
Tuesday, 20 June, 2017 - 11:00

Amphitheatre, Level 2, Duke-NUS

Speaker Details: 



Cancers driven by activating mutations of Ras are usually resistant to most currently-available treatment options and carry with them poor prognosis. Isoprenylcysteine carboxylmethyltransferase (Icmt), the enzyme catalyzing the last step of the prenylation pathway for proteins with C-terminal CaaX-motifs such as all common isoforms of Ras, has been investigated for its potential to be developed as a target for cancer therapy, especially for mutant Ras-driven cancers. Here, we report the biological effects of a novel Icmt inhibitor, Compound 8.12, developed as an improved version of the prototypical indole-based Icmt inhibtor, cysmethynil. Compound 8.12 treatment was found to result in the display of the hallmarks of Icmt inactivation in cells, result in cell cycle arrest and autophagy-dependent cell death, as well as improved reduction in cancer cell viability and xenograft tumor formation compared to cysmethynil. To further ascertain the role of Icmt in cancer initiation and   maintenance, we used a step-wise tumorigenesis model based on human mammary epithelial cells (HMECs) as well as established cancer cell lines and created Icmt loss-of-function cell lines using CRISPR/Cas9 technology. Icmt loss-of-function was found to significantly attenuate the transforming ability of all isoforms of mutant-Ras in pre-malignant HMECs, as well as significantly reducing the ability for Mia-PaCa-2 and MDA-MB-231 cells, both  established cancer cell lines harboring activating K-Ras mutations, to form tumors as subcutaneous xenografts in mice. The studies presented have provided important evidence supporting that i) Icmt is a valid target for cancer therapy, especially against mutant-Ras driven cancers; and ii) indole-based Icmt inhibitors, which are derivatives of cysmethynil, are potent agents against cancers in both in vitro and in vivo model systems and further investigations are warranted.

Thesis Advisor: Asst. Prof. Mei Wang-Casey