“The clinical benefits of BRAF inhibition in patients with advanced-stage BRAF-mutant melanoma are now well established. Although the emergence of cutaneous squamous-cell carcinomas (SCCs) and secondary melanomas in patients on BRAF-inhibitor therapy have been well described, reports are emerging of additional secondary premalignant and malignant events, including RAS-mutant leukaemia, the metastatic recurrence of RAS-mutant colorectal cancer and the development of gastric and colonic polyps.”
Good news for people with melanomas that have spread—the U.S. Food and Drug Administration just approved two new drugs that target tumors with common mutations. The drugs are dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), an MEK inhibitor. Developed by the pharmaceutical firm GlaxoSmithKline, both drugs target BRAF V600E mutations, which occur in about half of melanoma tumors. In addition, trametinib also targets V600K mutations, which are the next most common BRAF abnormalities. While these drugs have been tested in combination, using them together is not yet approved. The FDA also okayed a new test for the BRAF V600E mutation that is made by diagnostics firm bioMerieux.
“Using a panel of non–small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines.”
“Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines…”
“The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the MAPK pathway. Selective BRAF and MEK inhibitors have shown clinical efficacy in melanoma patients. However, the majority of responses are transient and resistance is often associated with pathway reactivation of the ERK signaling pathway. Here we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors…”
“Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers1, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF2. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals3, 4. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction…”
An experimental drug may strengthen treatments that target melanomas with mutations in the BRAF gene, reported researchers from the pharmaceutical company Merck at the American Association for Cancer Research’s 2013 meeting. Treatments that target BRAF often stop working because tumors activate a related protein called ERK, which is the target of Merck’s new drug. Called SCH772984, the drug inhibits ERK in cultured human tumor cells with BRAF, NRAS, or KRAS mutations; slows cell division in human tumor cells that resist treatments that target BRAF or MEK; and shrinks tumors in mice. The researchers have begun a phase I clinical trial of an ERK inhibitor in people with tumors.
“The mechanisms underlying adaptive resistance of melanoma to targeted therapies remain unclear. By combining ChIP sequencing with microarray-based gene profiling, we determined that ERBB3 is upregulated by FOXD3, a transcription factor that promotes resistance to RAF inhibitors in melanoma…”