Direct inhibition of RAS is not yet possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small-cell lung cancer (NSCLC).
Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF(V) (600E) melanoma.
Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma.
Finally, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression predicted significantly improved progression-free survival.
From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1).
Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events such as RTK activation, KRAS mutation, or NF1 loss-of-function mutations.
Here, we summarize and evaluate the human relevance of various RAF and RAS mouse melanoma models and their contribution to our understanding of melanoma.
Herein, we examined whether targeting the RAS-RAF-MEK-ERK pathway with the RAF inhibitor sorafenib and/or the PI3K-AKT-mTOR pathway with the mTOR inhibitor rapamycin has therapeutic effects against melanoma.
However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer.
If the response to RAF kinase inhibition is dependent on the presence of an activated BRAF protein, it will be necessary to evaluate cases of malignant melanoma for the presence or absence of BRAF mutations.
In clinical trials, the RAF inhibitor, PLX4032 (vemurafenib), caused partial or complete responses in 48-81% of mutant B-RAF harboring melanoma patients.
In conclusion, we report that (WT)BRAF/(WT)NRAS melanoma lines with low phospho-CRAF and high cAMP levels may be sensitive to vemurafenib and that CRAF inhibition through cAMP stimulation may overcome the resistance to the drug.
In order to better understand the mechanistic basis for this resistance, we conducted a RNAi-based screen to identify genes that mediated chemoresistance to the RAF kinase inhibitor RAF265 in a BRAF (V600E) mutant melanoma cell line that is resistant to this drug.
Inhibitors of RAF inhibit the MAPK pathway that plays an important role in the development and progression of those melanoma carrying the V600E BRAF mutation, but there's a subset of such patients who do not respond to the therapy.