Abstract 2613: MEK is a therapeutic and chemopreventative target in squamous cell carcinoma
Authors: Adelmann Charles H. , Truong Kimberly , Liang Roger , Bansal Varun , Saporito Rachael , Lee Woojin , Du Lili , Nicholas Courtney , Napoli Marco , Flores Elsa R. , Tsai Kenneth Y. 
Published: July 2016

Purpose: While the prognosis of cutaneous squamous cell carcinoma (cuSCC) is excellent overall, advanced metastatic disease represents a substantial mortality burden for which no standard targeted therapy exists. Findings from genomic and proteomic studies and the observed induction of cuSCC by BRAF inhibitor driven MEK/ERK pathway engagement suggest that MEK/ERK activation is essential for cuSCC tumorigenesis and tumor proliferation. Most cuSCC arise from a clinically and histopathologically defined preneoplastic precursor, the actinic keratosis (AK). Molecular studies of early events in cuSCC pathogenesis strongly implicate MEK/ERK signaling at the proteomic and transcriptional level. This occurs at the earliest recognizable transitions from chronically UV-exposed skin to AK, with sharp elevation of ETS2/ELK1 transcriptional target expression. With these compelling rationales in mind, we tested whether MEK inhibitors (MEKi) are a clinically actionable treatment and chemoprevention approach for cuSCC. Given that several MEKi are approved, this is a readily translated strategy.

Experimental Design: Preclinical testing was performed in 10 cuSCC cell lines and two mouse models of cuSCC using two distinct MEK inhibitors, trametinib and cobimetinib. We show that two MEKi, trametinib and cobimetinib are highly effective against cuSCC cell lines in culture, effectively engage MEK/ERK signaling in cells and in vivo, and potently induce cell cycle arrest and senescence. Both established and new tumors are powerfully inhibited in both xenograft and UV-driven autochthonous mouse models. This model, which utilizes immunocompetent SKH-1E mice exposed to chronic, low-dose, solar simulated UV light (12.5 kJ/m2 UVB weekly administered across three doses) more faithfully recapitulates human cuSCC molecularly than chemical carcinogenesis models. Lesions in this model exhibit heterogeneity in latency and responses to therapy, as do human tumors.

Results: MEK inhibitor treatment of cuSCC lines strongly reduces proliferation and induces senescence markers in cells, including p21 and beta-galactosidase. This response was universal, but highly heterogeneous. Sensitivity to MEKi was determined, in part, by modulation of AKT activity, and combination MEKi and AKTi. In-vivo, an SRB1 xenograft model was exquisitely sensitive to oral trametinib treatment, and in our spontaneous UV-driven Hairless mouse model of cuSCC, treatment with the MEK inhibitors trametinib and cobimetinib strongly reduced tumor growth and almost completely abrogated tumor induction. We confirmed target engagement in-vivo showing that ERK signaling was significantly suppressed.

Conclusions: Overall, we conclude MEK signaling is critical for cuSCC tumor induction and maintenance, and that MEK inhibition is an attractive approach for both advanced cuSCC treatment as well as chemoprevention.

Citation Format: Charles H. Adelmann, Kimberly Truong, Roger Liang, Varun Bansal, Rachael Saporito, Woojin Lee, Lili Du, Courtney Nicholas, Marco Napoli, Elsa R. Flores, Kenneth Y. Tsai. MEK is a therapeutic and chemopreventative target in squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2613.