Highlights of This Issue

Abstract

Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype. The study by Madak-Erdogan and colleagues establishes an estrogen receptor (ERα)/MAPK (ERK5)/Cofilin (CFL1) network that specifies the degree of breast cancer aggressiveness through coupling of actin reorganization and hormone receptor–mediated transcription. In ERα-positive cells, hormone activation resulted in the localization of ERK5 and CFL1 to active nuclear transcriptional hubs, whereas in ERα-negative cells, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion. The dynamic interplay of nuclear receptor–mediated transcription and actin reorganization through this ERα/ERK5/CFL1 axis suggests new prognostic biomarkers and novel therapeutic avenues to moderate cancer aggressiveness.Small cell lung cancer (SCLC) is a highly metastatic disease with significant mortality. Despite a role for RB and p53 involvement, evidence of PTEN pathway alterations is less well defined. The Rapid Impact article by Cui and colleagues reports the development of a novel metastatic mouse model which uses a sensitized model that harbors deletions in RB and p53 to delineate the functional role of PTEN. The PTEN pathway is mutated in a subset of human SCLC patients. Importantly, PTEN inactivation accelerated SCLC. Evidence also supports a role for PTEN in suppression of adenocarcinoma with neuroendocrine differentiation. Significant efforts are underway to bring inhibitors of PTEN pathway components such as AKT and PI3K to the clinic; these results suggest promise for such an approach in SCLC.Pharmacological blockade of HSP90 triggers a heat shock response that mitigates the full benefit of targeted agents to this ubiquitous chaperone protein. Using a chemical screen, Acquaviva and colleagues identify PI3K/mTOR inhibitors as a class of therapeutics that suppress nuclear translocation of heat shock factor 1 (HSF1) following treatment with the HSP90 inhibitor ganetespib. Mechanistically, this effect is regulated, in part, by mTOR-dependent translational activity. Moreover, combined regimens with mTOR or dual PI3K/mTOR inhibitors potentiate the anti-tumor efficacy of ganetespib in multiple in vivo models. These data identify a clinically feasible strategy to optimize the therapeutic benefit of HSP90 inhibitors.The p90 ribosomal S6 kinase (RSK) family is frequently expressed in a multitude of cancer types and its activity is important for the regulation of many critical biological outcomes, including cell survival, proliferation, and cell polarity. As such, effective inhibition of RSK activity is a promising therapeutic goal. Here, Aronchik and colleagues characterize the binding of two novel and closely related inhibitors to the RSK family kinase domain. Using a KinomeScan functional screen and crystallographic analysis, these novel inhibitors display a high degree of RSK selectivity. Furthermore, both inhibitors effectively suppressed phosphorylation of known RSK targets alone or in combination with AKT or mTOR inhibitors. Finally, cellular inhibition of RSK activity revealed heterogeneous and context-specific functions with regard to growth and survival.