Topical Dual PI3K–mTOR Inhibition with Bimiralisib in Actinic Keratosis: From Disease Models to Human Skin Pharmacology

Background/Objectives: Actinic keratosis (AK) is the most common precancerous cutaneous lesion and may progress through squamous cell carcinoma in situ (SCCIS) to cutaneous squamous cell carcinoma (cSCC). The PI3K–mTOR pathway is hyperactivated across this spectrum, yet no approved therapy targets it. We evaluated topical bimiralisib (PQR309), a pan-class I PI3K inhibitor with activity against mTOR, and developed a topical bimiralisib gel. Methods: K14-Fyn-Y528F transgenic mice received topical bimiralisib 1% (w/w) or a vehicle daily for 4 weeks, or 50 mg kg−1 orally. Human cSCC explants were incubated with bimiralisib 0.1–10 µmol L−1, and UV-B-irradiated SKH-1 mice received topical bimiralisib 3% (w/w), a vehicle or no treatment, with imiquimod as a comparator. Two of fourteen formulations underwent in vitro release and permeation testing as well as in vivo porcine penetration testing. Results: Topical bimiralisib reduced the lesion area by >99% at 4 weeks, restoring unremarkable epidermis and normalising PI3K–mTOR, MAPK and Src-family signalling without erythema or crusting, while oral dosing was inactive (mean reduction 35%; p ≥ 0.2). Phospho-Akt fell in a concentration-dependent manner in human explants, and lead gels delivered epidermal concentrations at or above the IC90 required for pathway inhibition. In the UV-B-irradiated SKH-1 model, topical bimiralisib prevented cSCC occurrence and Ki-67 labelling but did not reduce atypia in AKs or SCCIS. Conclusions: Activity is governed by epidermal drug exposure rather than intrinsic potency, supporting topical dual PI3K–mTOR inhibition as a non-inflammatory field-directed strategy for AK.