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

Our plain-English summary of Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma, by R. Kanteti, T. Mirzapoiazova, J.J. Riehm, et al (Cancer Biology & Therapy, 2018).

The study

• Authors: R. Kanteti, T. Mirzapoiazova, J.J. Riehm, I. Dhanasingh, B. Mambetsariev, J. Wang, P. Kulkarni, G. Kaushik, P. Seshacharyulu, M.P. Ponnusamy, H.L. Kindler, M.W. Nasser, S.K. Batra, R. Salgia
• Journal: Cancer Biology & Therapy
• Published: 2018;19(4):316-327
• Cited by: 77 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined focal adhesion kinase (FAK), a cell protein, in malignant pleural mesothelioma and pancreatic ductal adenocarcinoma. It did not treat patients or study asbestos exposure. Its only patient-tissue data were public gene-expression results from surgical samples. The authors used seven mesothelioma and six pancreatic cancer cell lines, a non-cancerous mesothelial line (Met-5A), and 3D tumor 'organoids' from a mouse model of pancreatic cancer. FAK protein was relatively high in the cancer lines compared with Met-5A. FAK mRNA, a measure of gene expression, was significantly higher in tumor samples than in normal tissue samples. Three experimental FAK-blocking drugs (PF-573228, PF-431396, VS-6063) significantly reduced cell viability in every mesothelioma cell line tested but not in Met-5A. In selected lines, depending on drug and dose, the drugs increased cell death, increased the share of cells held at the G2/M stage of cell division, and reduced colony formation. In organoids (15 per group), PF-573228 significantly reduced growth only at the higher of two doses (p = 0.03). The authors concluded that FAK is a therapy target meriting further translational studies. Live-animal tests were still under way.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cancer cell lines (in vitro), tumor organoids from a mouse model (ex vivo), and analysis of public gene-expression microarray data from surgical tissue samples
• Who was studied: Seven mesothelioma cell lines (H2596, H513, H2461, H2052, H2452, H28, H2373), one benign transformed mesothelial control cell line (Met-5A), and six pancreatic cancer cell lines, all from the American Type Culture Collection. Also tumor organoids from KrasG12D; Pdx-1 Cre (KC) mice, with 15 followed per group. Public microarray data came from samples obtained in patients who underwent surgery: normal pleura (n = 5), normal lung (n = 4), malignant pleural mesothelioma (n = 42), normal pancreas (n = 16) and pancreatic cancer (n = 36).
• Exposure: No asbestos exposure was studied. Cells and organoids were treated with three small-molecule FAK inhibitors: PF-573228 and PF-431396 (which also inhibit PYK2) and VS-6063 (which inhibits FAK but not PYK2).
• Main results:
  • FAK protein levels were relatively high in the mesothelioma and pancreatic cancer cell lines compared with the Met-5A control mesothelial cells
  • In public microarray data from surgical tissue samples, FAK mRNA was significantly higher in mesothelioma and pancreatic cancer samples than in the corresponding normal tissue samples
  • All three inhibitors significantly reduced cell viability in every mesothelioma cell line tested, but not in the Met-5A control cells. H2596, H2052 and H513 were the most sensitive. Most pancreatic cancer cell lines were also sensitive.
  • In H2596 mesothelioma cells, the lowest concentration of PF-431396 tested produced a two-fold increase in apoptotic (dying) cells. PF-573228 and VS-6063 at that concentration showed no discernible effect on apoptosis.
  • PF-431396 significantly arrested H2596 mesothelioma cells in the G2/M phase of the cell cycle at all concentrations tested. PF-573228 did so only at higher concentrations.
  • All three inhibitors reduced the number of soft-agar colonies formed by H2596 mesothelioma cells in a dose-dependent way. VS-6063 was the most effective, followed by PF-431396.
  • In the ECIS adhesion test on fibronectin, PF-573228 and PF-431396 significantly reduced the maximum electrical resistance of MiaPaca 2 and Capan 1 pancreatic cancer cells compared with vehicle
  • In mouse KC pancreatic tumor organoids (15 per group), PF-573228 decreased organoid size at both doses. The reduction was statistically significant (p = 0.03) only at the higher dose, at day four, compared with untreated controls.
• The authors' conclusion: The authors concluded that FAK is an important target for mesothelioma and pancreatic cancer therapy that merits further translational studies
• Limitations the authors state:
  • The authors noted significant variation between cell lines in whether higher FAK levels predicted greater sensitivity to the inhibitors
  • The authors stated that studies in live mouse xenograft models had not yet been done and were in progress
  • The authors noted that very few studies have examined the toxicity of these inhibitors in normal cells

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Adenocarcinoma, Apoptosis, Mesothelioma.

Related studies

• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells — T. Kato, T. Sato, et al. (2017)
• Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype — X. Ning, T.T.T. Nguyễn, et al. (2026)
• Expression of Calretinin, Marker of Mesothelial Differentiation, in Pancreatic Ductal Adenocarcinoma: A Potential Diagnostic Pitfall — G. Askan, O. Basturk (2021)
• Efficacy and immunogenic effects of Tumor Treating Fields (TTFields) in preclinical models of pancreatic ductal adenocarcinoma, with and without gemcitabine/nab-paclitaxel — T. Kan, T. Haj Khalil, et al. (2026)
• MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma — R. Kanteti, I. Dhanasingh, et al. (2014)

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