Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined.

NET Rounding: a novel approach to efficient and effective rounds for the modern clinical learning environment.

Background: Rounds are a foundational practice in patient care and education in the inpatient healthcare environment, but increased demands on inpatient teams have led to dissatisfaction with inefficient, ineffective rounds. In this study, we describe the design, implementation, and evaluation of a novel rounding framework ("NET Rounding") that provides behaviorally-based strategies to inpatient teams to achieve efficient rounds while preserving patient safety and education.

Methods: NET Rounding consists of nine recommendations divided into three categories: Novel rounding strategies, shared Expectations, and Time management.

Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in -Mutant Non-Small Cell Lung Cancer.

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in -mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone.

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in -mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity.