Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

• Published in: JNCI : Journal of the National Cancer Institute Vol. 107; no. 8; p. djv123
• Main Authors: François, Rony A, Maeng, Kyungah, Nawab, Akbar, Kaye, Frederic J, Hochwald, Steven N, Zajac-Kaye, Maria
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-08-2015
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzamides; Carcinoma - drug therapy; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Resistance, Neoplasm; Drug Synergism; Everolimus; Female; Focal Adhesion Kinase 1 - antagonists & inhibitors; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy - methods; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - metabolism; Organic Chemicals - pharmacology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Peritoneal Neoplasms - drug therapy; Protein Kinase Inhibitors - pharmacology; Pyrazines; Signal Transduction - drug effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Sulfonamides; TOR Serine-Threonine Kinases - antagonists & inhibitors; Up-Regulation; Xenograft Model Antitumor Assays
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djv123

Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.
We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.
We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.
We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration-approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.