FAK signaling in human cancer as a target for therapeutics

Our plain-English summary of FAK signaling in human cancer as a target for therapeutics, by B.Y. Lee, P. Timpson, L.G. Horvath, et al (Pharmacology & Therapeutics, 2015).

The study

• Authors: B.Y. Lee, P. Timpson, L.G. Horvath, R.J. Daly
• Journal: Pharmacology & Therapeutics
• Published: 2015;146:132-49
• Type of article: Review
• Cited by: 351 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.

Copyright © 2014 Elsevier Inc. All rights reserved.

In plain English

This article is a review, not an original study. The authors summarized published laboratory, animal and early clinical research on focal adhesion kinase (FAK), a signaling protein, and on drugs designed to block it in cancer. It did not study asbestos exposure; mesothelioma was one of many cancers discussed. Among the studies reviewed, one reported that malignant pleural mesothelioma cells with low levels of the protein merlin responded more to the drug VS-4718 in laboratory and xenograft models. The same study reported that VS-4718 preferentially eliminated cancer stem cells that had been enriched following pemetrexed and cisplatin treatment in a patient-derived xenograft model of mesothelioma. The review noted that a placebo-controlled phase II trial of the drug VS-6063 in malignant pleural mesothelioma, called COMMAND, was still recruiting. It also noted that a phase I study of GSK2256098 reported minor responses in some patients, including patients with mesothelioma. The authors concluded that much remains to be learned about which cancer types and stages suit these drugs and whether patients can be selected using biomarkers.

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: Narrative review of published laboratory, animal and clinical research on FAK signaling in cancer and on FAK-targeting drugs
• Who was studied: No people were studied directly. The review covered published preclinical (cell culture and animal) and clinical studies across many cancer types, including malignant pleural mesothelioma.
• Exposure: Not an asbestos exposure study. The 'exposures' reviewed were FAK-targeting drugs, including PF-00562271, VS-6063 (defactinib), VS-4718, GSK2256098, Y15 and BI 853520.
• Main results:
  • A cited study (Shapiro et al., 2014) reported that low expression of merlin predicted greater responsiveness of malignant pleural mesothelioma (MPM) cells to VS-4718, in vitro and in xenograft models.
  • In the same cited study (Shapiro et al., 2014), in a patient-derived xenograft model of mesothelioma, VS-4718 preferentially eliminated cancer stem cells that had been enriched after pemetrexed and cisplatin treatment.
  • A phase II randomized, double-blind, placebo-controlled trial of VS-6063 in malignant pleural mesothelioma (COMMAND) was recruiting in 12 countries at the time of writing. No results were reported.
  • Preliminary phase I results for GSK2256098 in patients with solid tumors reported minor responses in patients with mesothelioma, melanoma and nasopharyngeal cancer, and stable disease in renal cell carcinoma.
  • In a cited phase I trial of PF-00562271 in 99 patients with solid cancers, 14 patients were evaluated by PET scanning and 7 of these had metabolic responses.
  • In company-reported interim data on VS-6063 combined with paclitaxel in patients with ovarian cancer, 14 of 22 (64%) patients showed stable disease.
• The authors' conclusion: The authors concluded that much remains to be learned about which cancer types and stages are most appropriate for FAK inhibitors, and whether patients can be stratified for treatment using predictive biomarkers.

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Angiogenesis, STEM, Tyrosine Kinase Inhibitor, Biomarker, Merlin, Mesothelioma.

Related studies

• A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors — J.C. Soria, H.K. Gan, et al. (2016)
• The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma — V. Laszlo, Z. Valko, et al. (2019)
• Podoplanin: An emerging cancer biomarker and therapeutic target — H. Krishnan, J. Rayes, et al. (2018)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model — T.T. Van, M. Hanibuchi, et al. (2012)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)

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