2. Academic Validation
  3. The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells

The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells

  • Breast Cancer Res. 2016 Mar 24;18(1):37. doi: 10.1186/s13058-016-0694-4.
Israa Salem 1,  Manal Alsalahi 1,  Inna Chervoneva 2,  Lucy D Aburto 1,  Sankar Addya 3,  Gregory R Ott 4,  Bruce A Ruggeri 4 5,  Massimo Cristofanilli 1 6,  Sandra V Fernandez 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 2 Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
  • 3 Cancer Genomics Facility, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 4 Teva Branded Pharmaceutical Products R&D, West Chester, PA, USA.
  • 5 Present address: Incyte Pharmaceuticals, Wilmington, DE, USA.
  • 6 Present address: Department of Medicine - Hematology and Oncology, Robert H. Curie, Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
  • 7 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA. Sandra.Fernandez@jefferson.edu.
PMID: 27009091 DOI: 10.1186/s13058-016-0694-4
Abstract

Background: Inflammatory breast Cancer (IBC) is an aggressive type of advanced breast Cancer with a poor prognosis. We recently found that focal adhesion kinase 1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC.

Methods: Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple-negative breast Cancer non-IBC cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and phospho-ALK (Tyr 1604). In vivo, we tested CEP-37440 using FC-IBC02, SUM149, and SUM190 IBC xenograft mouse models.

Results: CEP-37440 at low concentration decreased the proliferation of the IBC cell lines FC-IBC02, SUM190, and KPL4, while not affecting the proliferation of normal breast epithelial cells. At higher concentration, CEP-37440 was also able to inhibit the proliferation of the IBC cell line MDA-IBC03 and the triple-negative non-IBC cell lines MDA-MB-231 and MDA-MB-468; the IBC cell line SUM149 showed a slight response to the drug. CEP-37440 decreased the cell proliferation of FC-IBC02, SUM190, and KPL4 by blocking the autophosphorylation kinase activity of FAK1 (Tyr 397). None of the cells evaluated expressed ALK. In vivo, after 7 weeks of CEP-37440 treatment, the SUM190, FC-IBC02, and SUM149 breast tumor xenografts were smaller in mice treated with 55 mg/kg bid CEP-37440 compared to the controls; the tumor growth inhibition (TGI) was 79.7 %, 33 %, and 23 %, respectively. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis while 20 % of the mice in the control group developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to Apoptosis, interferon signaling, and cytokines.

Conclusions: CEP-37440 is effective against some IBC cells that express phospho-FAK1 (Tyr 397), and its antiproliferative activity is related to its ability to decrease phospho-FAK1. Our results suggest that combinational therapies could be more effective than using CEP-37440 as a single agent.

Keywords

ALK; CEP-37440; FAK1; IBC; Inflammatory breast cancer; TNBC; Triple-negative breast cancer.

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