Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.

Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity

Understanding Somali piracy through cognitive resources theory

This paper examines Somali piracy through the lens of Cognitive Resources Theory (CRT). By and large, Somali piracy consists of hijacking ships, mostly in the Indian Ocean and adjacent areas, and collecting ransom money so as to fund future pirates’ operations. CRT postulates that stress is the enemy of rationality, harming a group’s ability to operate logically and analytically, and impacting both leadership and group performance. Cognitive resources refer to a group’s combined skills and its leader’s experience and decision-making abilities. Based on these cognitive resources, CRT asserts that levels of high and low stress affect a leader’s ability to employ his or her intelligence and experience. To carry out a smooth hijacking operation, a Somali pirate group must alleviate stress. It must have a leader with intelligence and experience to carry out a successful mission in situations of high stress. It is the leader’s responsibility to maintain group unity by providing a supportive, directive environment. As we will see in this analysis, one of the many ways to achieve group normalcy and commitment is by imposing the diya and heer codes – a long-established system of norms and honour within Somalian clans

Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors

Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. ClinicalTrials.gov NCT01358331. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633)

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase

An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue <b>1</b> that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound <b>4</b> as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound <b>4</b> to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which <b>4</b> can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity