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.”

Mutual Regulation Between Raf/MEK/ERK Signaling and Y-Box-Binding Protein-1 Promotes Prostate Cancer Progression

“Y-box-binding protein-1 (YB-1) is known to perform various functions related to cell proliferation, anti-apoptosis, and epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer.”

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).”

New Combination Treatment May Target Melanomas with BRAF Mutations Safely

While melanomas with BRAF mutations can be targeted with a combination of BRAF inhibitors and MEK inhibitors, the treatment can have side effects such as fever, light sensitivity, and rashes. But early results of a phase I clinical trial suggest that BRAF-mutant melanomas could be treated safely and effectively with a new combination: LGX818, a BRAF inhibitor developed by Novartis and MEK162, a MEK inhibitor developed by Array BioPharma. Moreover, using these drugs together may decrease common side effects of targeted BRAF treatments, including skin toxicities and muscle and joint pain. A phase III trial of this new combination treatment is expected to begin later in 2013.

Paradoxical Oncogenesis—The Long-Term Effects of BRAF Inhibition in Melanoma

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.”

2 Skin Cancer Drugs Win FDA Approval

“Two new drugs for metastatic or inoperable melanoma, dabrafenib (Tafinlar) and trametinib (Mekinist), were approved by the FDA on Wednesday.The agency also approved a companion diagnostic test for both agents to detect certain mutations in the BRAF gene that render melanoma cells susceptible to the drugs.”

Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS-Mutant Lung Cancer

“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.”

MEK Inhibition Affects STAT3 Signaling and Invasion in Human Melanoma Cell 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…”

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

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…”