Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

“Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.”


Outsmarting Drug Resistance in Melanomas

Melanomas commonly stop responding to targeted therapies, and a new study helps explain why. The researchers linked resistance to BRAF and MEK inhibitors in people with two genetic abnormalities: extra copies of BRAF-V600E, the most common melanoma mutation, as well as a new mutation called MEK2-Q60P. Encouragingly, the researchers also found that adding a third treatment (a PI3K inhibitor) to the mix makes melanomas stop growing in mice. While the team cautions that the solution is unlikely to be as simple of a triple inhibitor treatment for people, this work could help researchers find ways of overcoming drug resistance in melanomas.


Speedy Review for Melanoma Combo Treatment

The U.S. Food and Drug Administration (FDA) has granted a priority review of whether two melanoma drugs work better together. The drugs are a BRAF inhibitor called Tafinlar (dabrafenib) and a MEK inhibitor called Mekinist (trametinib); both are already FDA-approved for use separately. Tumors, however, often become resistant to BRAF inhibitors, growing back after an initial period of shrinking. The hope is that adding a MEK inhibitor will prevent this resistance. The FDA’s ruling on this combination targeted treatment is expected in January 2014.


How to Control Other Cancers Caused by Targeted Treatments for Melanoma

While effective against melanomas with BRAF mutations, BRAF inhibitors can also cause other cancers such as squamous cell carcinoma and RAS-mutant leukemia. In an overview of the field, researchers say that people treated with BRAF inhibitors may need long-term follow-ups. The researchers also suggest combining BRAF inhibitors with treatments that target the other cancers. These include MEK inhibitors, which control some but not all of the other cancers. In addition, people treated with BRAF inhibitors may need more aggressive screening if they have a family history of colorectal cancer.


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


FDA Asked to Approve New Combination Treatment for Melanoma

Two new drugs that target melanomas were approved by the US Food and Drug Administration in May, and the drug developer has already filed for approval to use them in combination. The drugs are dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), a MEK inhibitor, and both are made by GlaxoSmithKline. The combination treatment request is based on promising results of a Phase I/II trial, which showed that the two drugs work better together than dabrafenib does alone. Results of a Phase III trial of the combination therapy are expected later this year.


Phase II Study of Selumetinib (sel) Versus Temozolomide (TMZ) in Gnaq/Gna11 (Gq/11) Mutant (mut) Uveal Melanoma (UM)

“Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012).”