K-ras is different from N-Ras and H-Ras
- has stronger oncogenicity
- K-ras deletion is embryonic lethal in mice, but when replaced by H-Ras in genome locus, still viable
--> the K-Ras locus is important
K-Ras-4A, rather than 4B, is responsible for tumor initiation in lung cancer
G12C - most common K-Ras mutation in lung cancer
G12C and G12V - prefer RalGDS pathway
G12D - prefer Raf-MAPK/PI3K pathway
lung adenocarcinoma
- G12C and G12V have worse outcome than G12D
Ras mutation cancers are excluded from target therapy
- lung: erlotinib
- colorectal : cetuximab *** but G13D CRC mutation benefits from cetuximab addition
- Improved in PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68)
- melanoma- N-Ras mutation, exclude from vemurafenib
- Ras superfamily proteins share identical or near-identical effector-binding proteins, but only H-Ras, N-Ras, and K-Ras are capable of binding and activating Raf kinases
- R-Ras can bind and activate PI3K, but rare
-neurofibromin, a GAP, tumor suppressor, contributes to Ras hyperactivation
- Ras initiates cancer : okay
- but tumor maintenance: ? less clear
When can't we just target Ras and end it once and for all?
- genetic ablation of Ras led to rebound hyperactivation of EGFR (normally suppressed by hyperactivation of Ras)- research on increasing the intrinsic GTPase activity of Ras to decrease mutant Ras activity
Ras when geranylgeranylated will function normally
- K-Ras, N-Ras can be geranylgeranylated even when farnesyltransferase is inhibited, thus, will farnesyltansferase inhibition is not useful
- H-Ras, not geranylgeranylated, can be farnesylatransferase inhibited
- palmitoylation of K-Ras-4A, N-Ras, H-Ras (for membrane localization) may have therapeutic potential
- K-Ras-4B with PDE6sigma - modulates K-Ras to cellular membrane
- inhibition of PDE6sigma inhibits further downstream signaling
- monoubiquitination at Lys147 enhances Ras GTP loading
- Lys104 acetylation - decrease GEF-induced nucleotide exchange --> reduced transformation
- SIRT2 and HDAC6 regulates aceylation level of K-Ras --> these 2 enzymes may play oncogenic role
- H-Ras Cys118 nitrosylation --> higher level GTP bound
-eNos protein : enhancer of nitrosylation --> may be therapeutic target
Downstream Pathways and Targets
- the search for drugs blocking Ras activity move to its downstream
- Raf inhibitors --> cause paradoxical activation of Raf-kinase
- MEK and ERK are downstreams of Raf, but MEK and ERK inhibition does not inhibit Ras activity
--> because MEK and ERK inhibitor relieves other feedback inhibiton --> PI3K then activates
MEK1 and ERK2 are embryonic lethal --> limited therapeutic windows (無法把isoforms都抑制)
- sorafenib (c-Raf inhibitor, VEGFR, PDGFR inhibito)
- phase II clinical trial- phospho-ERK or VEGFR activity correlation with clinical outcome still unclear
- PI3K inhibitors still not good outcome due to feedback mechanisms + poor therapeutic index
- in mouse, ablation of c-Raf inhibits Ras-driven lung adenoCa
- in pancreatic mouse model, B-Raf only required for tumor proression
--> tissue specific signaling
other potential targets
- RalGDS - mice null for RalGDS have reduced skin carcinogen-induced tumor
- CDK4 inhibitor --> lung adenoCA reduced growth
- STK33, TBK1, GATA-2
- STK33 so far not useful target in K-Ras-driven tumor
-GATA2- abalation in mice reduce lung adenoCA --> therapeutic promising
參考文獻
