Off‐targets effects underlie the inhibitory effect of FAK inhibitors on platelet activation: studies using Fak‐deficient mice

Roh, Michelle E.; Cosgrove, Megan E.; Górski, Karol; Hitchcock, Ian S.

doi:10.1111/jth.12343

Cited by 12 publications

(13 citation statements)

References 14 publications

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“…Consistently, defects in human GPVI-mediated aggregation, calcium mobilization and dense granule (ATP) secretion have also been reported using the FAK inhibitor, PF-228 [26]. More recently however, comparable effects of PF-228 were reported in FAK deficient platelets in in vitro (platelet aggregation) and in vivo (carotid occlusion artery) assays relative to wild type mice [27]. Interestingly, studies on Pyk2-deficient platelets demonstrate no significant differences in in vitro GPVI-induced platelet responses (aggregation, α-granule secretion and spreading).…”

Section: Introductionsupporting

confidence: 54%

Role of Focal Adhesion Tyrosine Kinases in GPVI-Dependent Platelet Activation and Reactive Oxygen Species Formation

et al. 2014

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BackgroundWe have previously shown the presence of a TRAF4/p47phox/Hic5/Pyk2 complex associated with the platelet collagen receptor, GPVI, consistent with a potential role of this complex in GPVI-dependent ROS formation. In other cell systems, NOX-dependent ROS formation is facilitated by Pyk2, which along with its closely related homologue FAK are known to be activated and phosphorylated downstream of ligand binding to GPVI.AimsTo evaluate the relative roles of Pyk2 and FAK in GPVI-dependent ROS formation and to determine their location within the GPVI signaling pathway.Methods and ResultsHuman and mouse washed platelets (from WT or Pyk2 KO mice) were pre-treated with pharmacological inhibitors targeting FAK or Pyk2 (PF-228 and Tyrphostin A9, respectively) and stimulated with the GPVI-specific agonist, CRP. FAK, but not Pyk2, was found to be essential for GPVI-dependent ROS production and aggregation. Subsequent human platelet studies with PF-228 confirmed FAK is essential for GPVI-mediated phosphatidylserine exposure, α-granule secretion (P-selectin (CD62P) surface expression) and integrin αIIbβ3 activation. To determine the precise location of FAK within the GPVI pathway, we analyzed the effect of PF-228 inhibition in CRP-stimulated platelets in conjunction with immunoprecipitation and pulldown analysis to show that FAK is downstream of Lyn, Spleen tyrosine kinase (Syk), PI3-K and Bruton's tyrosine kinase (Btk) and upstream of Rac1, PLCγ2, Ca2+ release, PKC, Hic-5, NOX1 and αIIbβ3 activation.ConclusionOverall, these data suggest a novel role for FAK in GPVI-dependent ROS formation and platelet activation and elucidate a proximal signaling role for FAK within the GPVI pathway.

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Section: Introductionsupporting

confidence: 54%

Role of Focal Adhesion Tyrosine Kinases in GPVI-Dependent Platelet Activation and Reactive Oxygen Species Formation

et al. 2014

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“…S4a ). Although a specific tyrosine kinase inhibitor of FAK significantly represses tumor malignancy, as our unpublished data and others have reported 36 37 , off-target effects are a concern due to the potential side effects of clinical therapeutics 36 . Here, the inhibitory efficacy of the FAK/25aa peptide, a non-tyrosine kinase inhibitor of FAK tyrosine activity that targets β4 integrin/FAK complex formation, is supported as a suitable therapeutic strategy.…”

Section: Discussionmentioning

confidence: 60%

An EGFR/Src-dependent β4 integrin/FAK complex contributes to malignancy of breast cancer

Tai

Chu

Lai

et al. 2015

Sci Rep

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β4 integrin and focal adhesion kinase (FAK) are often associated with a poor prognosis in cancer patients, and their signaling events have recently been linked to malignant outcomes. Here, we demonstrate, for the first time, physical and functional interactions between β4 integrin and FAK that influence breast cancer malignancy. An amino-terminal linker within FAK is essential for its binding with the cytodomain of β4 integrin. Moreover, EGFR/Src-signaling triggers the tyrosine phosphorylation of β4 integrin, which, in turn, recruits FAK to β4 integrin and leads to FAK activation and signaling. Upon disruption of the β4 integrin/FAK complex, tumorigenesis and metastasis in triple-negative breast cancer were markedly reduced. Importantly, the concomitant overexpression of β4 integrin and FAK significantly correlates with malignant potential in patients with triple-negative breast cancer. This study describes a pro-metastatic EGFR/Src-dependent β4 integrin/FAK complex that is involved in breast cancer malignancy and is a novel therapeutic target for triple-negative breast cancer.

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“…FAK, on the other hand, is a candidate for targeting, as FAK inhibitors have been developed and are currently being evaluated in the context of tumor initiation, growth, and metastasis 49 . However, FAK is essential in numerous normal cellular processes, and while FAK inhibition may alter NANOG activity, it is likely to be associated with adverse clinical complications 62 – 64 . Our current study suggests that targeting Cx26 may be an effective alternative to targeting both FAK and NANOG, as modulating Cx26 expression and function disrupt the critical Cx26/NANOG/FAK ternary complex that is vital for non-TNBC tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase

et al. 2018

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Tumors adapt their phenotypes during growth and in response to therapies through dynamic changes in cellular processes. Connexin proteins enable such dynamic changes during development, and their dysregulation leads to disease states. The gap junction communication channels formed by connexins have been reported to exhibit tumor-suppressive functions, including in triple-negative breast cancer (TNBC). However, we find that connexin 26 (Cx26) is elevated in self-renewing cancer stem cells (CSCs) and is necessary and sufficient for their maintenance. Cx26 promotes CSC self-renewal by forming a signaling complex with the pluripotency transcription factor NANOG and focal adhesion kinase (FAK), resulting in NANOG stabilization and FAK activation. This FAK/NANOG-containing complex is not formed in mammary epithelial or luminal breast cancer cells. These findings challenge the paradigm that connexins are tumor suppressors in TNBC and reveal a unique function for Cx26 in regulating the core self-renewal signaling that controls CSC maintenance.

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Off‐targets effects underlie the inhibitory effect of FAK inhibitors on platelet activation: studies using Fak‐deficient mice

Cited by 12 publications

References 14 publications

Role of Focal Adhesion Tyrosine Kinases in GPVI-Dependent Platelet Activation and Reactive Oxygen Species Formation

Role of Focal Adhesion Tyrosine Kinases in GPVI-Dependent Platelet Activation and Reactive Oxygen Species Formation

An EGFR/Src-dependent β4 integrin/FAK complex contributes to malignancy of breast cancer

Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase

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