Evolutionarily conserved dual lysine motif determines the non-chaperone function of secreted Hsp90alpha in tumour progression.

Both intracellular and extracellular heat shock protein-90 (Hsp90) family proteins (α and ß) have been shown to support tumour progression. The tumour-supporting activity of the intracellular Hsp90 is attributed to their N-terminal ATPase-driven chaperone function. What molecular entity determines the extracellular function of secreted Hsp90 and the distinction between Hsp90α and Hsp90ß was unclear. Here we demonstrate that CRISPR/Case9 knocking out Hsp90α nullifies tumour cells' ability to migrate, invade and metastasize without affecting the cell survival and growth. Knocking out Hsp90ß leads to tumour cell death. Extracellular supplementation with recombinant Hsp90α, but not Hsp90ß, protein recovers tumourigenicity of the Hsp90α-knockout cells. Sequential mutagenesis identifies two evolutionarily conserved lysine residues, lys-270 and lys-277, in the Hsp90α subfamily that determine the extracellular Hsp90α function. Hsp90ß subfamily lacks the dual lysine motif and the extracellular function. Substitutions of gly-262 and thr-269 in Hsp90ß with lysines convert Hsp90ß to a Hsp90α-like protein. Newly constructed monoclonal antibody, 1G6-D7, against the dual lysine region of secreted Hsp90α inhibits both de novo tumour formation and expansion of already formed tumours in mice. This study suggests an alternative therapeutic approach to target Hsp90 in cancer, that is, the tumour-secreted Hsp90α, instead of the intracellular Hsp90α and Hsp90ß.

A review of clinical trials of biologic agents and small molecules for psoriasis in Asian subjects.

INTRODUCTION: Biologics are increasingly used in the treatment of moderate to severe psoriasis. However, most of the pivotal studies were performed mainly in western countries. The purpose of this review article was to compare the differences of clinical trial results between Asian and Western subjects of psoriasis regarding baseline demographics, efficacy, dermatology life quality index, safety and antidrug antibodies. EVIDENCE ACQUISITION: In this review article, we searched the PubMed/Medline, ClinicalTrials.gov, and posters from main dermatologic meetings. EVIDENCE SYNTHESIS: Only randomized controlled trial results or trial results for registration purposes of etanercept, adalimumab, infliximab, ustekinumab, secukinumab, brodalumab, ixekizumab, guselkumab, tofacitinib, and apremilast are included. CONCLUSIONS: Asian subjects were generally 15-20 Kgs lighter, with fewer psoriatic arthritis, shorter disease duration since diagnosis, and higher baseline severity compared to western subjects. Better efficacy had been found in some studies such as secukinumab, brodalumab, ixekizumab, and tofacitinib in Japanese groups. The safety in Asian trials was generally compatible with the pivotal studies, except for the occurrence of active tuberculosis in the infliximab trial in China. Additional indications of pustular and erythrodermic psoriasis are approved in Japan for some of the agents based on phase II/III studies.