Is heat shock protein 90 inhibition a relevant treatment strategy for psoriasis?
Authors: Hervé Bachelez
Journal: British Journal of Dermatology (2022)

Linked Article: Bregnhøj et al. Br J Dermatol 2022; 186:861–874. Over recent decades, several targeted therapies – biologics and small molecules – have been successfully developed and approved for the treatment of moderate-to-severe psoriasis vulgaris. This intense development has been driven by compelling evidence for the major pathogenic contributions of key inflammatory effector cytokines such as tumour necrosis factor (TNF)-α and the interleukin (IL)-23–IL-17 family axis.1 Among the key regulators of TNF-α- and IL-17-driven inflammatory pathways lies heat shock protein (HSP)90, a protein playing major functions in physiology and in carcinogenesis.2 In this issue of the BJD, Bregnhøj et al. report results from a proof-of-concept, phase Ib study investigating the safety and efficacy of the novel HSP90 inhibitor RGRN-305 in 11 patients with plaque psoriasis over 12 weeks.3 Although RGRN-305 was primarily developed for cancer, serendipitous observation of psoriasis remission in one patient, and alleviation of psoriasis-like inflammation in a xenografted mouse model provided a rationale for this study. Administered orally at two dosages (250 and 500 mg daily), the drug was associated with ≥50% improvement of Psoriasis Area and Severity Index (range 71–94%) at 12 weeks vs. baseline in six of 11 patients, without a clear dose effect. The authors also conducted skin transcriptome analysis using microarrays, showing early and sustained reduction of TNF-α- and IL-17-induced inflammatory transcripts with pathophysiological relevance, including IL36G and CXCL8, and delayed downregulation of IL23/STAT3-driven activities in clinical responders. However, the impacts of HSP90 are likely to be broader, and obviously beyond keratinocytes. In in vitro studies of a THP-1 monocytic cell line, HSP90 inhibition has been shown to reduce pyroptosis, a proinflammatory mode of cell death, through alteration of the NLRP3 inflammasome.4 NLRP3 gene polymorphisms have been reported to increase the risk of developing psoriasis in the Swedish population,5 but evidence for a central contribution of the NLRP3 inflammasome in human psoriasis is still missing. Therefore it would be interesting to complement studies showing alleviation by RGRN-305 of TNF-α- and IL17-driven inflammatory transcripts in keratinocytes, with assessment of its capacity to alter the NLRP3 inflammasome in different cellular subtypes. As this target cannot be accurately investigated by transcriptome studies, such research may open perspectives in other immune-mediated skin diseases.6 However, safety concerns related to HSP90 inhibition should not be neglected, given their broad physiological functions that are in line with their multiple protein–protein interactions. Likewise, the adverse events reported by Bregnhøj et al. in their study sound like a warning, with eczema-like skin rashes reported in four of the five patients receiving the higher dose, while only mild adverse events were observed in the lower-dose group. Taken together, these results still carry the promise for a new mode of action in psoriasis. Whether HSP90 inhibitors will fill remaining gaps in the context of a broader and more diversified set of oral and biologic therapies for psoriasis is not clear yet. However, with the development of precision medicine approaches, there is no doubt that innovative targeted drug development still has a future in psoriasis, and that new relevant modes of action will continue to emerge.