Letters to the Editor
Janus kinase inhibitors – holistically seeing two faces
- John A Loudon, Paul Kubler, d4bb942bb920ddcf
- Aust Prescr 2015;38:3-4
- 1 February 2015
- DOI: 10.18773/austprescr.2015.006
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Editor, - I was interested to read the recent article on Janus kinase inhibitors by Paul Kubler (Aust Prescr 2014;37:154-7). In addition to being pro-cancer, the Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is part of a central physiological pro-survival mechanism.1 Thus pharmacological targeting of this signalling cascade may pose potential threats, for example to cardiac integrity.2 Targeting JAK-STAT will also potentially challenge neuroprotection.3 Conversely, activation of JAK-STAT is proposed as a tangible approach to managing heart disease.4
The message is that there is a clinically highly relevant ‘crossroads’ between physiology and cancer, thus maintaining the truly holistic viewpoint. Therefore treatments aimed at targeting cancer necessarily target normal tissues and in turn define burgeoning fields within cancer-related therapy such as cardio-oncology. Activating a pro-survival pathway such as JAK-STAT therapeutically to manage heart disease removes a barrier in the multiple-step process of oncogenesis. Targeting the JAK-STAT pathway is in a sense ‘non-specifically specific’. The target may be a defined one, but the target itself is universally expressed.
Future developments in therapeutics must be designed to be ‘specifically specific’ to the disease target to be effective, yet with little fear of resultant adverse reaction.
John A Loudon
Baulkham Hills NSW
Although there is a large volume of published data about the JAK-STAT pathway, it is mostly pre-clinical. Currently, very few drugs targeting Janus kinase signalling have been approved by regulatory authorities and are in clinical use. The focus of the article was on those mechanisms which have current clinical applications.
The statement of whether specifically targeting selective errors of the immune system (that is being specifically specific) versus inhibiting multiple cytokines (that is being non-specifically specific) is a better way of improving effectiveness and reducing adverse effects, is a vexed question with no clear answer. The clinical data in the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus do not consistently support this hypothesis. The patho-aetiology of many autoimmune diseases is characterised by multiple abnormalities of the immune system with cascading effects over time and alternative pathways of disease perpetuation after onset, hence I would suggest specifically specific therapies are less likely to be effective from a biological plausibility perspective as the disease progresses. If we could identify and treat disease in a pre-clinical phase, specifically specific therapies have the potential to be more effective. However, the answer to this is unknown.
Dental practitioner, Baulkham Hills, NSW