AKT1 Activation is Obligatory for Spontaneous BCC Tumor Growth in a Murine Model that Mimics Some Features of Basal Cell Nevus Syndrome

作者：Kim Arianna L^*; Back Jung Ho; Zhu Yucui; Tang Xiuwei; Yardley Nathan P; Kim Katherine J; Athar Mohammad^*; Bickers David R^*

来源：Cancer Prevention Research, 2016, 9(10): 794-802.

DOI：10.1158/1940-6207.CAPR-16-0066

Patients with basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, develop numerous basal cell carcinomas (BCC) due to germline mutations in the tumor suppressor PTCH1 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-Ptch1(+/-) 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 Ptch1(+/-) mice in the absence of carcinogenic stimuli. Introducing Akt1 haplodeficiency in Ptch1(+/-) mice (Akt1(+/-)Ptch1(+/-)) 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.

• 出版日期2016-10