Highlights of This Issue

Abstract

Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in the clinic. This study, discovered that amplification and overexpression of a cell cycle associated kinase called Tousled-like kinase 2 (TLK2) mechanistically impairs Chk1/2-induced DNA-damage checkpoint signaling, leading to a G2/M checkpoint defect, delayed DNA repair process, and increased CIN. This is the first report linking TLK2 function to CIN, which yields new insight into the deregulated DNA damage pathway and increased genomic instability in aggressive luminal breast cancers. Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers.Oncogenic mRNA translation, in part, is controlled by MAPK-interacting kinases (MNKs) through phosphorylation of the mRNA-binding protein eIF4E. Bell and colleagues provide evidence that the MNK pathway is upregulated in mesenchymal subtype glioblastoma. Pharmacological inhibition of the pathway using the small-molecule inhibitor merestinib blocked translation of oncogenic mRNAs in glioblastoma and glioma stem cells. Moreover, merestinib disrupted glioma stem cell frequency in vitro and prolonged survival in an intracranial xenograft mouse model. These findings provide a rationale for targeting mRNA translation in the therapy-resistant, mesenchymal, cancer stem cell (CSC) population in glioblastoma.The Rac activator PREX1 was previously established as a driver of melanoma invasion and metastasis. In the current study, Ryan and colleagues now identify the mechanism of PREX1 activation. Pharmacologic inhibition of the ERK mitogen-activated protein kinases reduced PREX1 protein expression in melanoma at the level of transcription and protein stability. Suggesting that ERK regulated PREX1 expression in melanoma represents a novel mechanism of regulation, which contrasts with the mechanisms that cause PREX1 overexpression in prostate and breast cancers. Finally, together with missense mutations in Rac and the related PREX2 protein in melanomas, these findings implicate a third mechanism for Rac activation in melanoma.Drug-induced reactivation of survival signaling pathways is a key mechanism of drug resistance and treatment failure to kinase inhibitors. In order to discover such adaptive resistance mechanisms, Kim and colleagues leveraged a mass spectrometry-based approach to enumerate MEK inhibitor-induced changes in the phosphoproteome in KRAS-mutant lung cancer cells. Results revealed a gain of receptor tyrosine kinases (RTK) phosphorylation, with multiple MEK pathway inhibitors, which promotes microenvironment-induced growth factor signaling through AKT in KRAS-mutant lung cancer. Broadly, these results suggest a new avenue by which MEK inhibitors rewire cancer circuits enabling adaptive resistance.