GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth

Journal Article · Sat Sep 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.07.139· OSTI ID:23105536

Ding, Ling-tao ^[1]; Zhao, Peng; Yang, Min-lie; Lv, Guo-zhong ^[2]; Zhao, Tian-lan ^[1]

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1. Department of Plastic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou (China)
2. Department of Burns and Plastic Surgery, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu (China)

Highlights: • GDC-0084 is a novel small-molecule PI3K/mTOR dual inhibitor. • GDC-0084 inhibits cutaneous squamous cell carcinoma (cSCC) cell survival/proliferation. • GDC-0084 induces apoptosis activation in cSCC cells. • GDC-0084 blocks PI3K-Akt-mTOR and DNA-PKcs signaling activation in cSCC cells. • Gastric gavage of GDC-0084 inhibits A431 xenograft tumor growth in SCID mice. 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.

• OSTI ID: 23105536
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3 Vol. 503; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

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