GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth
- Biochem Biophys Res Commun. 2018 Sep 10;503(3):1941-1948. doi: 10.1016/j.bbrc.2018.07.139.
- 1. Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China; Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu, China.
- 2. Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu, China.
- 3. Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu, China. Electronic address: [email protected].
- 4. Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: [email protected].
GDC-0084 is a novel and potent small-molecule PI3K-mTOR dual inhibitor. The present study examined its potential activity in cutaneous squamous cell carcinoma (cSCC) cells. Our results show that GDC-0084 treatment at nanomole concentrations potently inhibited survival and proliferation of established (A431, SCC-13 and SCL-1 lines) and primary human cSCC cells. GDC-0084 induced Apoptosis activation and cell cycle arrest in the cSCC cells. It was more efficient than Other known PI3K-Akt-mTOR inhibitors in killing cSCC cells, but was non-cytotoxic to the normal human skin fibroblasts/keratinocytes. In A431 cells and primary cSCC cells, GDC-0084 blocked phosphorylation of key PI3K-Akt-mTOR components, including p85, Akt, S6K1 and S6. GDC-0084 also inhibited DNA-PKcs activation in cSCC cells. Significantly, restoring DNA-PKcs activation by a constitutively active-DNA-PKcs (S2056D) partially inhibited GDC-0084-induced cell death and Apoptosis in A431 cells. In vivo, GDC-0084 daily gavage potently inhibited A431 xenograft tumor growth in mice. In GDC-0084-treated tumor tissues PI3K-Akt-mTOR and DNA-PKcs activation were significantly inhibited. In summary, GDC-0084 inhibits human cSCC cell growth in vitro and in vivo through blocking PI3K-Akt-mTOR and DNA-PKcs signalings.