The TCI Clinical Encounter Program for PhD Students in Cancer Biology: a Feasibility Pilot.

Clinical rotations are often not included in graduate-level cancer biology curricula; however, basic insight into clinical oncology is often crucial for developing translational research that addresses unmet needs with the potential to benefit cancer patients. We describe a needs assessment, design, implementation, and descriptive evaluation of an oncology-specific pilot clinical encounter program developed for PhD students in the Cancer Biology Training Area (CAB) in the Graduate School of Biomedical Sciences (GSBS) and Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai (ISMMS). Prior to the development of this pilot program, CAB students, in years 2-5 + , were surveyed to determine their interest in a structured clinical experience. Seventeen out of thirty-one students responded (55%) to the survey. Of those seventeen respondents, fifteen (88.2%) expressed that exposure to cancer patients in the clinical setting would be useful for their pre-doctoral biomedical science and cancer biology training and indicated an interest in participating in the clinical encounter program. Based on these responses, a three-session clinical encounter pilot program was designed. Two separate cohorts of 5 students participated in this pilot program. During a formal debrief, following the clinical experience, students commented on the resilience of patients and the importance of research on clinical decision making, and reported that they found the experience motivational. Five out of 10 students responded (50%) to a post-program assessment survey; all five respondents answered that they would recommend the clinical encounter program to their peers. While limited in size and scope, this pilot TCI Clinical Encounter Program proved feasible and has the potential to enrich and inform the experience of PhD students pursing advanced degrees in a cancer biology.

Type II Binders Targeting the "GLR-Out" Conformation of the Pseudokinase STRADα.

Pseudokinases play important roles in signal transduction and cellular processes similar to those of catalytically competent kinases. However, pseudokinase pharmacological tractability and conformational space accessibility are poorly understood. Pseudokinases have only recently been suggested to adopt "inactive" conformations or interact with conformation-specific kinase inhibitors (e.g., type II compounds). In this work, the heavily substituted pseudokinase STRADα, which possesses a DFG → GLR substitution in the catalytic site that permits nucleotide binding while impairing divalent cation coordination, is used as a test case to demonstrate the potential applicability of conformation-specific, type II compounds to pseudokinase pharmacology. Integrated structural modeling is employed to generate a "GLR-out" conformational ensemble. Likely interacting type II compounds are identified through virtual screening against this ensemble model. Biophysical validation of compound binding is demonstrated through protein thermal stabilization and ATP competition. Localization of a top-performing compound through surface methylation strongly suggests that STRADα can adopt the "GLR-out" conformation and interact with compounds that comply with the standard type II pharmacophore. These results suggest that, despite a loss of catalytic function, some pseudokinases, including STRADα, may retain the conformational switching properties of conventional protein kinases.

Structural basis for the action of the drug trametinib at KSR-bound MEK.

The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology1, and more recently in immunotherapy2,3 and ageing4. However, many MEK inhibitors are limited owing to on-target toxicities5-7 and drug resistance8-10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.

Ploidy Leads a Molecular Motor to Walk Different Paths to Drug Resistance.

In this issue of Cell Chemical Biology, Pisa et al. (2020) find that haploid and diploid cells differentially develop resistance to the CENP-E inhibitor GSK923295. The results highlight the power of tumor cells to evade growth inhibition and potentially inform the design of next-generation CENP-E drugs to overcome resistance.

Elevated glycohemoglobin HbA1c is associated with low back pain in nonoverweight diabetics.

BACKGROUND CONTEXT: Low back pain (LBP) is a common complaint in clinical practice of multifactorial origin. Although obesity has been thought to contribute to LBP primarily by altering the distribution of mechanical loads on the spine, the additional contribution of obesity-related conditions such as diabetes mellitus (DM) to LBP has not been thoroughly examined. PURPOSE: To determine if there is a relationship between DM and LBP that is independent of body mass index (BMI) in a large cohort of adult survey participants. STUDY DESIGN: Retrospective analysis of prospectively collected National Health and Nutrition Examination Survey (NHANES) data to characterize associations between LBP, DM, and BMI in adults subdivided into 6 subpopulations: normal weight (BMI 18.5-25), overweight (BMI 25-30), and obese (BMI >30) diabetics and nondiabetics. Diabetes was defined with glycohemoglobin A1c (HbA1c) ≥6.5%. PATIENT SAMPLE: 11,756 participants from NHANES cohort. OUTCOME MEASURES: Percentage of LBP reported. METHODS: LBP reported in the 1999-2004 miscellaneous pain NHANES questionnaire was the dependent variable examined. Covariates included HbA1c, BMI, age, and family income ratio to poverty as continuous variables as well as race, gender, and smoking as binary variables. Individuals were further subdivided by weight class and diabetes status. Regression and graphical analyses were performed on the study population as a whole and also on subpopulations. RESULTS: Increasing HbA1c did not increase the odds of reporting LBP in the full cohort. However, multivariate logistic regression of the 6 subpopulations revealed that the odds of LBP significantly increased with increasing HbA1c levels in normal weight diabetics. No other subpopulations reported significant relationships between LBP and HbA1c. LBP was also significantly associated with BMI for normal weight diabetics and also for obese subjects regardless of their DM status. CONCLUSIONS: LBP is significantly related to DM status, but this relationship is complex and may interact with BMI. These results support the concept that LBP may be improved in normal weight diabetic subjects with improved glycemic control and weight loss, and that all obese LBP subjects may benefit from improved weight loss alone.

A whole-animal platform to advance a clinical kinase inhibitor into new disease space.

Synthetic tailoring of approved drugs for new indications is often difficult, as the most appropriate targets may not be readily apparent, and therefore few roadmaps exist to guide chemistry. Here, we report a multidisciplinary approach for accessing novel target and chemical space starting from an FDA-approved kinase inhibitor. By combining chemical and genetic modifier screening with computational modeling, we identify distinct kinases that strongly enhance ('pro-targets') or limit ('anti-targets') whole-animal activity of the clinical kinase inhibitor sorafenib in a Drosophila medullary thyroid carcinoma (MTC) model. We demonstrate that RAF-the original intended sorafenib target-and MKNK kinases function as pharmacological liabilities because of inhibitor-induced transactivation and negative feedback, respectively. Through progressive synthetic refinement, we report a new class of 'tumor calibrated inhibitors' with unique polypharmacology and strongly improved therapeutic index in fly and human MTC xenograft models. This platform provides a rational approach to creating new high-efficacy and low-toxicity drugs.