RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Abstract

Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine.

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

“…Evidences have shown that Ras mutations frequently occur in glioma. And Ras mutation leads to the activation of a wide range of signaling pathways, including AKT [23], which participate in controlling tumor cells proliferation, death, metastasis, and cell-cycle progression. This here, we found that AKT activation induced by Ras mutation led to the down-regulation of H1.5T10ph, but has no impacts on H1.5 expression.…”

Colorectal cancer mutational profiles correlate with defined microbial communities in the tumor microenvironment

“…Changes in this bacterial taxon's abundance has also been found to be associated with prostate cancer, although the mechanism of action is unknown [59] . We also show that mutations in KMT2C , a gene commonly co-mutated along with KRAS, could be predicted, in part, using the abundance of Ruminococcus [60] . These bacteria have been previously implicated in inflammatory bowel disorders and colorectal cancer by multiple groups [8,[61][62][63] .…”

RAF-MEK-MAPK Pathway Targeted by Tumor Suppression and Anticancer Therapeutic Agents

“…Tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib acting as reversible inhibitors for binding to the ATP pocket of the protein tyrosine kinase were clinically approved agents targeting EGFR. In NSCLC, gefitinib was shown to induce partial responses (PR) in approximately 10% of cases [46]. The downstream kinases were also tested as target for therapeutic intervention, resulting in the development of several potent MEK inhibitors [47,48].…”