Inhibition of Ras for Cancer Treatment: The Search Continues

Abstract

Background The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Discussion Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer. Conclusions Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

“…Development of anti-RAS therapeutic agents has turned towards targeting elements downstream of RAS, mainly either the PI3K or MAPK pathways (13)(14)(15). While several such approaches have been moderately effective, recent efforts have focused on preclinical evaluation of combination therapies.…”

“…However, effective small-molecule inhibitors for direct RAS inhibition has proven to be challenging due to difficulty in locating targetable binding pockets on the surface. Moreover, targeting RAS by blunting post-translational events such as farnesyl-transferase inhibitors showed promising initial preclinical results but ultimately led to poor clinical significance (14). This has prompted efforts at targeting RAS effectors, most notably in either the RAF/MEK/ERK or PI3K/AKT/mTOR pathways.…”

Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

“…Efforts to develop drugs that specifi cally block the activity of oncogenic Ras have been unsuccessful, although this remains an active area of investigation ( 10,11 ). Clinical studies show that oncogenic KRAS mutations predict resistance to EGF receptor (EGFR) inhibitors; hence, the use of RTK inhibitors in this subset of cancers is usually contraindicated ( 12 ).…”

Systems-wide Analysis of K-Ras, Cdc42, and PAK4 Signaling by Quantitative Phosphoproteomics

“…Approximately thirty percent of human tumors harbor a somatic gain-of-function mutation in one of three RAS genes, resulting in the constitutive activation of Ras signaling and the aberrant hyperactivation of growth-promoting effector pathways (1). Designing therapeutic agents that directly target Ras has been challenging (2,3), and thus clinical development efforts have focused on targeting effector pathways downstream of Ras. The Raf-MEK-ERK and PI3K-Akt effector pathways have been extensively studied and several small molecule inhibitors targeting these pathways are currently under clinical evaluation (4,5).…”