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Structure of skin and hair follicles and the effects of multikinase inhibitors on the skin

Effects of multikinase inhibitors in skin – Hand-foot skin reaction

In terms of HFSR pathophysiology, the most well studied multikinase inhibitors are sorafenib and sunitinib which target RAF (sorafenib only), c-KIT, fms-related tyrosine kinase receptor 3 (Flt3), VEGFR, and PDGFR kinases, inhibiting tumour-related angiogenesis and tumour growth.1 It has been hypothesised that hand-foot skin reaction may occur with these agents because keratinocytes in the epidermis synthesize PDGF-α and PDGF-β, which bind PDGFRs on dermal fibroblasts, capillaries, and eccrine glands. 1-2 In addition, dermal eccrine glands also express c-KIT and PDGFR, both of which are targets of sorafenib.1-2 Coinhibition of VEGFR and PDGFR could therefore potentially decrease the ability of vessels to repair themselves in high pressure areas of the hands and feet prevent vascular repair mechanisms from functioning properly, thereby causing HFSR in high-pressure areas, such as the palms and soles, which may be repeatedly exposed to subclinical trauma.3 

References

  1. 1. Lacouture ME, et al. The Oncologist. 2008;13:1001–1011.
  2. 2. Gomez P and Lacouture M. The Oncologist. 2011;16:1508–1519.
  3. 3. Robert C, et al. Lancet Oncol. 2005;6:491–500.

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