Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma

Rajani Kanteti, Tamara Mirzapoiazova, Jacob J. Riehm, Immanuel Dhanasingh, Bolot Mambetsariev, Jiale Wang, Prakash Kulkarni, Garima Kaushik, Parthasarathy Seshacharyulu, Moorthy Palanimuthu Ponnusamy, Hedy L. Kindler, Mohd W Nasser, Surinder Kumar Batra, Ravi Salgia

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)316-327
Number of pages12
JournalCancer Biology and Therapy
Volume19
Issue number4
DOIs
StatePublished - Apr 3 2018

Fingerprint

Focal Adhesion Protein-Tyrosine Kinases
Pancreatic Neoplasms
Organoids
Adenocarcinoma
Cell Line
Neoplasms
Focal Adhesion Kinase 2
Therapeutics
Mesothelioma
Growth
Cell Cycle Checkpoints
Electric Impedance
Fibronectins
Protein-Tyrosine Kinases
Cell Movement
Malignant Mesothelioma
Catalytic Domain
Cell Death
Phosphorylation
Apoptosis

Keywords

  • FAK
  • PF-431396
  • PF-573228
  • VS-6063
  • mesothelioma
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Kanteti, R., Mirzapoiazova, T., Riehm, J. J., Dhanasingh, I., Mambetsariev, B., Wang, J., ... Salgia, R. (2018). Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. Cancer Biology and Therapy, 19(4), 316-327. https://doi.org/10.1080/15384047.2017.1416937

Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. / Kanteti, Rajani; Mirzapoiazova, Tamara; Riehm, Jacob J.; Dhanasingh, Immanuel; Mambetsariev, Bolot; Wang, Jiale; Kulkarni, Prakash; Kaushik, Garima; Seshacharyulu, Parthasarathy; Palanimuthu Ponnusamy, Moorthy; Kindler, Hedy L.; Nasser, Mohd W; Batra, Surinder Kumar; Salgia, Ravi.

In: Cancer Biology and Therapy, Vol. 19, No. 4, 03.04.2018, p. 316-327.

Research output: Contribution to journalArticle

Kanteti, R, Mirzapoiazova, T, Riehm, JJ, Dhanasingh, I, Mambetsariev, B, Wang, J, Kulkarni, P, Kaushik, G, Seshacharyulu, P, Palanimuthu Ponnusamy, M, Kindler, HL, Nasser, MW, Batra, SK & Salgia, R 2018, 'Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma', Cancer Biology and Therapy, vol. 19, no. 4, pp. 316-327. https://doi.org/10.1080/15384047.2017.1416937
Kanteti, Rajani ; Mirzapoiazova, Tamara ; Riehm, Jacob J. ; Dhanasingh, Immanuel ; Mambetsariev, Bolot ; Wang, Jiale ; Kulkarni, Prakash ; Kaushik, Garima ; Seshacharyulu, Parthasarathy ; Palanimuthu Ponnusamy, Moorthy ; Kindler, Hedy L. ; Nasser, Mohd W ; Batra, Surinder Kumar ; Salgia, Ravi. / Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma. In: Cancer Biology and Therapy. 2018 ; Vol. 19, No. 4. pp. 316-327.
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