The Role of the Hedgehog Pathway Inhibitors in Hair Loss

So-called ‘hedgehog pathway inhibitors’ (HPI) such as vismodegib and sonidegib are effective therapies for treating basal cell carcinoma (BCC). HPI target overactive signals in the hedgehog molecular pathway that lead to the proliferation of cancer cells. However, when inhibiting the cancer cells, HPI also inhibit hair follicle (HF) growth which leads to hair loss in treated patients.

A recent review looked at experimental data on hair biology and the development of BCC and discussed the molecular steps involved in both processes. Hedgehog pathway signaling is activated in the skin in order to develop hair follicles for normal hair growth. There are key molecular events that occur in normal hair cycling and they mirror the molecular events that are involved in both BCC pathogenesis and the alopecia caused by HPI. Specifically, the interaction of Shh and Wnt/b-catenin signaling not only occurs during HF morphogenesis and normal hair cycling, but is also observed in oncogenic processes such as BCC development. HPI-induced hair loss is due to Shh inhibition which prevents HFs from transitioning to the anagen phase after shedding of hair in the telogen phase.

One result of better understanding this pathway and its role, may be the development of HPI that can recognize and then selectively block the Shh pathway in normal HFs to prevent alopecia. Since this adverse effect is one that leads patients to terminate use of HPIs, an advancement based on this concept might allow patients to continue HPI treatment for BCC.