Highlights of This Issue

The identification of novel targets preferentially expressed on tumors is paramount to the continued development of antibody-drug conjugates (ADCs) and similar relevant technologies. In this manuscript, Merlino and colleagues outline a C-type lectin, CD205, as a differentially expressed cell surface receptor for multiple cancer types. After characterizing a first-in-class ADC targeted at CD205, they demonstrate its activity against murine xenograft and PDX models of triple-negative breast, pancreatic, and bladder cancer. The ADC was most effective against TNBC, where four out of six PDX mice displayed lasting complete responses. Their ongoing clinical study will seek to translate this therapeutic into patients with CD205-positive metastatic solid tumors and relapsed or refractory non-Hodgkin's lymphoma.

Accumulating evidence has implicated deregulated translation initiation as a critical mechanism underlying the development and maintenance of hematologic malignancies. Despite recent advances in our understanding of the role that signaling pathways can play in modulating the activity of various translational components, there are still major gaps in our knowledge of oncogenic translational perturbations. Herein, Kapadia and Gartenhaus provide a concise overview on the newly identified deubiquitinases, which regulate the protein levels of key translational effectors driving tumor growth and promoting survival of hematological malignancies.

Using X-ray crystallography, Anantharajan and colleagues identify the mechanism of action of an allosteric inhibitor of Eya2, a tyrosine phosphatase often mis-expressed in cancers. Inhibitor binding results in a conformational change of the Eya2 α1-β1 loop (apo structure in grey; compound-bound structure in cyan), resulting in a shift of three key residues (dark blue) to a conformation that can no longer coordinate the Mg⁺² critical for catalysis. This inhibitor is on target in lung cancer cells and represents a highly specific and novel inhibitor of Eya2 that can be used as a chemical probe and developed into a potential therapeutic.

Intratumoral heterogeneity is thought to contribute to therapeutic resistance in GBM. McKinney and colleagues demonstrate that EGFR inhibition leads to altered oxidative stress, increased lipid peroxidation, and generation of toxic lipid peroxidation products. An ALDH-high subpopulation of cells, however, demonstrated resistance to EGFR inhibition, with decreased oxidative stress, decreased cell death, and increased invasiveness. In paired human GBM before and after EGFR inhibitor therapy there was an increase in ALDH expressing cells. Therapeutic strategies targeting both EGFR and this ALDH-high subpopulation may be particularly useful in GBM.