Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells

Hiscox, Stephen Edward; Barnfather, Peter; Hayes, Edward Raymond; Bramble, Pamela; Christensen, James G.; Nicholson, Robert Ian; Barrett-Lee, Peter

doi:10.1007/s10549-010-0857-4

Cited by 35 publications

(27 citation statements)

References 53 publications

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“…Such a hypothesis is supported by recent reports that pharmacological inhibition of FAK phosphorylation at Y397 using the FAK inhibitor PND-1186 has no effect in 2D cell culture, but increases apoptosis in 3D culture and in vivo . In contrast to proliferative responses, the role of FAK in cell migration is widely established (reviewed in Mitra et al (2005)), and many studies including the present study report that the inhibition of FAK activity suppresses breast cancer migration and invasion in vitro (Hiscox et al 2011) and metastasis in vivo . Interestingly, in contrast to MDA-361 cells, BT-474 cells were not responsive to the migration-promoting effects of heregulin.…”

Section: Discussionmentioning

confidence: 62%

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro¹,

Smith

Goddard

et al. 2013

Endocrine-Related Cancer

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The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ERC)/HER2C breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ERC/HER2K (MCF7 and T47D) and ERC/HER2C (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878Gtrastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ERC/HER2C cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ERC/HER2C cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ERC/HER2C breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ERC/HER2C, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

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Section: Discussionmentioning

confidence: 62%

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro¹,

Smith

Goddard

et al. 2013

Endocrine-Related Cancer

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“…Our conclusion is supported by the observation that PF reduces integrin-related FAK-p-Tyr 397 and paxillin-p-Tyr 118 but not the Nrg1␤-induced phosphorylation of FAK at Tyr 861 . Differential inhibition by PF of these two phosphorylation events has also been reported for lung and breast cancer cells (28,33). Thus, Nrg1␤ induces FAK phosphorylation independently of the classical integrin pathway.…”

Section: E789 Nrg1␤ Promotes Glucose Uptakementioning

confidence: 62%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308 and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473 but does not modify AS160-p-Thr642 or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473 phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

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“…This protein promotes cell survival (10). Inhibition of FAK phosphorylation could account for the observed decrease in cell growth, since the phosphorylation of FAK promotes cell survival and proliferation (14)(15)(16). To better understand the growth inhibitory effects of PF573,228 on these vascular tumor cells, the morphology of the cells was studied.…”

Section: Effects Of Pf573228mentioning

confidence: 99%

PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation

Mabeta

2016

Acta Pharmaceutica

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, and abrogated the phosphorylation of cell survival proteins, proline-rich Akt substrate (PRAS40) and S6 ribosomal protein (S6RP). Array data further revealed that PF573,228 induced caspase-3 activation, thus promoting apoptosis. Since all the processes inhibited by PF573,228 provide important support to tumor survival and progression, the drug may have a potential role in the treatment of vascular tumors.

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Inhibition of focal adhesion kinase suppresses the adverse phenotype of endocrine-resistant breast cancer cells and improves endocrine response in endocrine-sensitive cells

Cited by 35 publications

References 53 publications

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

PF573,228 inhibits vascular tumor cell growth, migration as well as angiogenesis, induces apoptosis and abrogates PRAS40 and S6RP phosphorylation

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