Question

why inhibitors that prevent plasma membrane localization of Ras have been used in clinical trials for treatment of several tumors, including colon cancer.

Answer 1

It has been noticed and verified that many of the human tumors arise from mutations that encode a RAS protein to stimulate signaling cascades necessary for malignant transformation, including cellular proliferation, survival and invasiveness, tumor angiogenesis, and metastasis. The RAS family is composed of 36 human genes, but KRAS, NRAS, and HRAS by far play the most prominent roles in human cancer. Due to this the inhibition of RAS protein becomes necessary.There has been several approaches to inhibit RAS focused on disrupting the post-translational lipid modifications of for maturation and localization of RAS to the plasma membrane.

It was noticed that the noncatalytic δ-subunit of the cyclic GMP phosphodiesterase 6 isozyme(chaperone), binds the prenyl group and shuttles RAS to the plasma membrane. A small-molecule inhibitor of PDEδ (deltarasin) inhibited KRAS signaling and pancreatic tumor cell growth in vitro and in vivo. Just like deltarasin, there have been many other inhibitors which have been used in clinical treatment for several tumors. These inhibiors prevents the plasma membrane localisation of Ras, which further stops the GTP hydrolysis followed by inhibition of metastatis, tumor angionensis, and malignant transformation.

Please give a thumbs up if the answer helped you. Thankyou!