Activation and involvement of Ral GTPases in colorectal cancer.

Martin TD, Samuel JC, Routh ED, Der CJ, Yeh JJ. "Cancer Res. 2011 Jan"

Current approaches to block KRAS oncogene purpose concentrate on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor action of selumetinib (AZD6244, ARRY-142886), a powerful and selective MEK1/2 inhibitor, on the panel of colorectal carcinoma (CRC) cells and identified no inhibition of KRAS mutant CRC cell anchorage-independent development.

Although AKT action was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent therapy with selumetinib didn't give further antitumor exercise. Consequently, we speculated that inhibition in the Ral guanine exchange aspect (RalGEF) effector pathway may possibly be a far more efficient strategy for blocking CRC growth.

RalGEFs are activators from the associated RalA and RalB modest GTPases and we identified activation of each in CRC cell lines and affected individual tumors. Interfering RNA steady suppression of RalA expression lowered CRC tumor cell anchorage-independent development, but remarkably, secure suppression of RalB greatly improved soft agar colony measurement and formation frequency. Regardless of their opposing actions, each RalA and RalB regulation of anchorage-independent growth needed interaction with RalBP1/RLIP76 and components from the exocyst complex.

Interestingly, RalA interaction using the Exo84 but not Sec5 exocyst component was essential for supporting anchorage-independent development, while RalB interaction with Sec5 although not Exo84 was essential for inhibition of anchorage-independent growth. We suggest that anti-RalA-selective therapies could provide an powerful strategy for KRAS mutant colorectal carcinoma (CRC).