Patients with basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, develop numerous basal cell carcinomas (BCCs) due to germline mutations in the tumor suppressor <i>PTCH1</i> and aberrant activation of Hedgehog (Hh) signaling. Therapies targeted at components of the Hh pathway, including the smoothened (SMO) inhibitor vismodegib, can ablate these tumors clinically, but tumors recur upon drug discontinuation. Using SKH1-<i>Ptch1<sup>+/-</sup></i> as a model that closely mimics the spontaneous and accelerated growth pattern of BCCs in patients with BCNS, we show that AKT1, a serine/threonine protein kinase, is intrinsically activated in keratinocytes derived from the skin of newborn <i>Ptch1<sup>+/-</sup></i> mice in the absence of carcinogenic stimuli. Introducing <i>Akt1</i> haplodeficiency in <i>Ptch1<sup>+/-</sup></i> mice (<i>Akt1<sup>+/-</sup> Ptch1<sup>+/-</sup></i>) significantly abrogated BCC growth. Similarly, pharmacological inhibition of AKT with perifosine, an alkyl phospholipid AKT inhibitor, diminished the growth of spontaneous and UV-induced BCCs. Our data demonstrate an obligatory role for AKT1 in BCC growth, and targeting AKT may help reduce BCC tumor burden in BCNS patients.
- Received March 2, 2016.
- Revision received June 8, 2016.
- Accepted June 28, 2016.
- Copyright ©2016, American Association for Cancer Research.