Highlights of This Issue

Abstract

Using liquid chromatography/mass spectrometry (LC/MS)-based metabolomics and the MEK inhibitor RO4987655, 21 plasma metabolite markers of MEK inhibition in two sensitive BRAF mutant, human melanoma xenograft models were identified. Of these, it was found that on-treatment changes in the concentrations of 15 metabolites significantly predicted objective responses in patients with advanced melanoma treated with RO4987655. In patients with progressive disease, it was demonstrated that propionyl carnitine and amino acid levels increased; while in those patients that responded, phosphatidylcholines and sphingomyelin concentrations decreased. In addition, the pre-treatment levels of seven plasma metabolites (phosphatidylcholines and sphingomyelins) had significant prognostic value.Given the lack of meaningful clinical efficacy of pharmacological agents targeting the IGF pathway when applied in unselected cancer patients, the identification of selection biomarkers is of crucial importance. Sanderson and colleagues report that autocrine IGF2 overexpression hyperactivates the IGF pathway in colorectal cancer (CRC) and other cancers and predicts for sensitivity to the IGF1R/INSR inhibitor BI 885578, either as monotherapy or in combination with VEGF-pathway inhibition. Coupled with the identification of substantial subsets of IGF2-overexpressing patients in diverse tumor types, these findings support the assessment of IGF2 expression for patient selection in future trials of IGF pathway inhibitors.Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but most patients eventually develop acquired resistance. Here, Shien and colleagues have identified that the IL6 family cytokine oncostatin-M (OSM) induced a switch to the epithelial-to-mesenchymal phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner, and co-targeting inhibition of the oncogenic pathway and JAK1 revered resistance to targeted drugs. These results suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target.OPCML, a GPI anchored tumor-suppressor protein is a negative regulator of receptor tyrosine kinases (RTK), is inactivated by somatic methylation in many cancer types. Here, Zanini and colleagues report that restoration of OPCML in deficient cells leads to sensitization to anti-HER RTK inhibitors. OPCML interacts with HER2 and not EGFR, thereby disrupting formation of HER2-EGFR heterodimers leading to better response to both lapatinib and erlotinib in HER2-expressing cancer cell lines. High OPCML expression is associated with better clinical response to lapatinib therapy in breast cancer patients. These results suggest that OPCML/RTK inhibitor co-therapy could be a valuable sensitizing approach to RTK inhibitors.