The Crosstalk between FAK and Wnt Signaling Pathways in Cancer and Its Therapeutic Implication

Our plain-English summary of The Crosstalk between FAK and Wnt Signaling Pathways in Cancer and Its Therapeutic Implication, by J. Wörthmüller, C. Rüegg (International Journal of Molecular Sciences, 2020).

The study

• Authors: J. Wörthmüller, C. Rüegg
• Journal: International Journal of Molecular Sciences
• Published: 2020;21(23)
• Type of article: Review
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk between both signaling pathways during development and tumor progression. A number of FAK-Wnt interactions are described, suggesting an intricate, context-specific, and cell type-dependent relationship. During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/β-catenin signaling pathway during APC-driven intestinal tumorigenesis. In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt. In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa. As the identification of effective Wnt inhibitors to translate in the clinical setting remains an outstanding challenge, further understanding of the functional interaction between Wnt and FAK could reveal new therapeutic opportunities and approaches greatly needed in clinical oncology. In this review, we summarize some of the most relevant interactions between FAK and Wnt in different cancers, address the current landscape of Wnt- and FAK-targeted therapies in different clinical trials, and discuss the rationale for targeting the FAK-Wnt crosstalk, along with the possible translational implications.

In plain English

This article was a review of published laboratory research on how two cell-signaling pathways, focal adhesion kinase (FAK) and Wnt, interact in cancer. It did not study asbestos or any fiber exposure. The authors described findings from other studies in colorectal, lung, breast, ovarian and other cancers, and in malignant mesothelioma. For mesothelioma, they cited a laboratory study in mesothelioma cell lines. In those cells, blocking FAK activated Wnt signaling, blocking Wnt activated FAK, and blocking both together drastically reduced cell growth and survival. They also reviewed clinical trials of drugs aimed at each pathway. Two Wnt inhibitors led to bone problems, including more fractures. FAK inhibitors had manageable side effects but did not produce objective clinical responses, and several trials of the FAK inhibitor defactinib in mesothelioma were stopped for insufficient efficacy. The authors concluded that FAK appears to regulate Wnt signaling, that the interactions depend on context and cell type, and that better understanding is needed before designing combination treatments. They noted the picture remains far from complete.

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 studies and clinical trials
• Who was studied: No new subjects were studied. The review covered published research on FAK and Wnt interactions in development and in several cancers, including colorectal, lung, breast, ovarian, liver, prostate and renal cancer, leukemia, melanoma, and malignant mesothelioma. Separately, it covered clinical trials of FAK and Wnt inhibitors.
• Exposure: Not applicable. The review concerns drugs and cell-signaling pathways and does not discuss asbestos or any fiber exposure.
• Main results:
  • In a cited study of malignant mesothelioma cell lines, a FAK inhibitor activated the Wnt pathway, and Wnt inhibition in the same cells activated FAK. This indicated that the two pathways oppose each other.
  • In that cited work, blocking FAK and Wnt at the same time drastically reduced proliferation and survival of the mesothelioma cell lines.
  • In a cited laboratory study, lowering calretinin made mesothelioma cells more susceptible to the FAK inhibitor defactinib. The cells that survived were more resistant to chemotherapy because the Wnt pathway was activated.
  • In a cited phase I trial, the FAK inhibitor GSK2256098 showed clinical activity in patients with malignant mesothelioma, particularly those with merlin (NF2) loss.
  • Several trials of defactinib in patients with malignant mesothelioma were discontinued because of insufficient efficacy.
  • Across the clinical trials reviewed, FAK inhibitors had manageable toxicity and some effect on progression-free survival and stable disease, but did not produce objective clinical responses.
  • The Wnt inhibitors vantictumab and ipafricept were in principle well tolerated, but caused bone metabolism disorders, including an increased incidence of fractures in patients.
• The authors' conclusion: The authors concluded that FAK appears to be an important regulator of Wnt signaling. They found that FAK and Wnt interactions vary by context and cell type, and stated that a better understanding is needed before combination treatments are designed. They considered targeting FAK, or both pathways together, a promising strategy.
• Limitations the authors state:
  • The authors stated that the overall picture of FAK and Wnt crosstalk, especially in specific cancers, is still far from comprehensive.
  • The authors stated that they could not cite all relevant published work because of the article's selective focus and space limits.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Mesothelioma, Clinical Trial.

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• 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)
• Loss of NF2 Induces TGFβ Receptor 1-mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome — J.H. Cho, A.Y. Oh, et al. (2018)
• Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma — J. Wang, T. Mirzapoiazova, et al. (2018)
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