Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling. Mol Cancer Ther 2016 May;15(5):985-97
Date
03/05/2016Pubmed ID
26939707Pubmed Central ID
PMC4873426DOI
10.1158/1535-7163.MCT-15-0717Scopus ID
2-s2.0-84969522621 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
We and others have recently shown cisplatin resistance-related protein 9 (CRR9)/Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) to affect survival and proliferation in lung and pancreatic tumor cells. Our research has indicated that CLPTM1L affects multiple survival signaling pathways in tumor cells under oncogenic, genotoxic, and microenvironmental stress. We have confirmed the association of CLPTM1L with pancreatic cancer by demonstrating overexpression of CLPTM1L in pancreatic tumors and poor survival in patients with high tumor expression of CLPTM1L. Predicting a transmembrane structure, we determined that CLPTM1L could be targeted at the plasma membrane. Herein, we describe the development of mAbs targeting CLPTM1L. Lead antibodies inhibited surface accumulation of CLPTM1L, Akt phosphorylation, anchorage-independent growth, and chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and p110α in pancreatic tumor cells, which was inhibited by anti-CLPTM1L. In vivo treatment with anti-CLPTM1L robustly inhibited the growth of both lung and pancreatic adenocarcinoma xenografts. The efficacy of anti-CLPTM1L correlated with specific epitopes representing important targets in human cancers, particularly those driven by KRas, for which effective targeted therapies have been elusive. This study is the first to report cell-surface exposure of the tumor survival protein CLPTM1L and inhibition of the function of surface CLPTM1L with novel, systematically developed inhibitory mAbs establishing proof of concept of clinically practical agents inhibiting this compelling new tumor survival target in cancer. Mol Cancer Ther; 15(5); 985-97. ©2016 AACR.
Author List
Puskás LG, Mán I, Szebeni G, Tiszlavicz L, Tsai S, James MAMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antineoplastic Agents
Cell Line, Tumor
Cell Membrane
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic
Disease Models, Animal
Drug Resistance, Neoplasm
Gene Expression
Humans
Membrane Proteins
Mice
Neoplasm Proteins
Neoplasms
Phosphatidylinositol 3-Kinases
Phosphorylation
Prognosis
Protein Binding
Proto-Oncogene Proteins c-akt
Signal Transduction
Xenograft Model Antitumor Assays
