Cancer Biology & Therapy 2018 January 5 [Epub ahead of print] [Link]
Kanteti R, et. al.
Abstract
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.
January 11, 2018
- adenocarcinoma
- (add-en-o car-sin-o-muh). Cancer that starts in the glandular tissue, such as in the ducts or lobules of the breast.
- apoptosis
- a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- therapy
- any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.
- tumor
- an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).
Mesothelioma Line Administrator