Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

Abstract

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 disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, 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. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

“…Existing MEK inhibitors lack specificity against oncogenic KRAS versus BRAF mutations that converge on the MAPK signaling pathway. We studied the novel MEK inhibitor GDC-0623, which has been shown to have superior efficacy against KRAS compared with BRAF mutant tumors (10). We found that GDC-0623 treatment can potently up-regulate BIM and to a greater extent than observed for other MEK inhibitors that have undergone clinical evaluation (32,33).…”

“…In contrast to BRAF mutant melanomas, this limited efficacy indicates that different mechanisms of inhibition are required for optimal antitumor activity in each genotype. Structural and functional analyses indicate that the novel MEK inhibitor GDC-0623 can achieve superior efficacy in KRAS-driven tumors by forming a strong hydrogen bond interaction with Ser 212 in MEK that is critical for blocking MEK feedback phosphorylation by wildtype RAF (10). On the basis of favorable preclinical data, GDC-0623 is currently being studied in a phase I clinical trial.…”

Antibody-Mediated Delivery of Anti–KRAS-siRNA In Vivo Overcomes Therapy Resistance in Colon Cancer

“…Unfortunately, despite the long available knowledge about mutant KRAS, no successful therapeutic approaches have entered clinical practice. One targetable molecule MEK might help to block signaling downstream of mutated RAS and several inhibitors of MEK are currently in clinical trials (6,7,37). Only recently, a new MEK inhibitory substance was reported to rescue cetuximab resistance in KRAS-mutated colorectal cancer cell lines (38).…”

“…These include MEK, PI3K, and AKT inhibitors. Most of these drugs are still in early clinical trials (5)(6)(7).…”

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

“…Another phenomenon is priming, which can lead to activation via kinase inhibitors, which has been observed for several kinases like AKT, MEK, and JAK (Okuzumi et al, 2009;Andraos et al, 2012;Hatzivassiliou et al, 2013). Priming describes the up-regulation of the phosphorylated form of the targeted kinase upon inhibition, which can lead to an activation of the pathway once the inhibitor is removed.…”