FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

Timbrell, Simon; Aglan, H; Cramer, Angela; Foden, Phil; Weaver, David T.; Pachter, Jonathan A.; Kilgallon, Aoife; Clarke, Robert B.; Farnie, Gillian; Bundred, Nigel

doi:10.1038/s41523-021-00263-3

Cited by 22 publications

(24 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, in 2D, we found pFAK, ERK1/2 kinase upstream in the integrin signaling are downregulated in PF1-SID. This is consistent with the activation of these kinase proteins in cohort of invasive breast cancer that confirmed high FAK expression is correlated with increased risk of recurrence and reduced survival in invasive breast cancer [57] . Modulation of these biological processes is also linked with EMT in concordance with previously shown role of PF1 in blocking EMT and established role of SID decoys in suppressing invasion [ 11 , 58 ].…”

Section: Discussionsupporting

confidence: 86%

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Kadamb¹,

Leibovitch²,

Farías³

et al. 2022

Translational Oncology

View full text Add to dashboard Cite

Highlights We show that the PAH2 domain of SIN3A is a target when it is inhibited from binding to PF1 results in inhibition of invasive phenotype in TNBC. Epigenetic repression of integrins expression and downstream pathways results from enhanced binding of KLF9 /SIN3A repressor complex to their promoters. Genome wide transcriptomic analysis showed downregulation of multiple invasion related genes. Tumor growth and lung metastasis were markedly decreased in vivo. Our studies highlight that PF1 might serve as a gatekeeper for trafficking SID protein binding to PAH2 of SIN3A and has functional role in presentation of different regulatory complexes. Blocking the function of PAH2 offers a promising targeted therapy approach for inhibiting the invasive phenotype in TNBC.

show abstract

Section: Discussionsupporting

confidence: 86%

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Kadamb¹,

Leibovitch²,

Farías³

et al. 2022

Translational Oncology

View full text Add to dashboard Cite

show abstract

“…This led to STAT3 nuclear accumulation and increased TNBC cell invasiveness, which could be reduced by using the FAK inhibitor VS-4718 [ 89 ]. In another cohort of invasive TNBC patient samples, high FAK expression was shown to correlate with an increased risk of cancer recurrence and reduced patient survival [ 90 ]. Moreover, co-expression of FAK and markers of cancer stem cells (CSCs), which are known to contribute to therapy resistance and disease recurrence, was associated with poor prognosis [ 90 ].…”

Section: Other Strategies To Target Fak In Pancreatic and Other Cancersmentioning

confidence: 99%

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Murphy

Zhu

Trpceski

et al. 2022

Biochemical Society Transactions

View full text Add to dashboard Cite

The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or ‘priming’) via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.

show abstract

“…Accordingly, our results provide one plausible explanation for why deleting 1 integrin in the MEC basal population so dramatically reduces basal progenitor activity in the tissue to favor luminal differentiation 76 , and why deleting FAK in the entire breast epithelium so potently impairs luminal and basal progenitor cell function 77 . Our findings could also explain links between 1 integrin signaling and FAK activity and breast tumor aggression and metastasis [78][79][80][81][82][83][84][85][86][87] . Indeed, given that a basal-like luminal progenitor cell was recently identified and that HER2-positive and basal-like human breast cancers are thought to originate from luminal progenitor MEC populations 88,89 , this raises the possibility that 1 integrin mechanosignaling favors the emergence of aggressive mesenchymallike breast cancer subtypes by expanding a pool of basal-like progenitor MECs.…”

Section: Discussionmentioning

confidence: 62%

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression

Northey

Yui

Hayward

et al. 2022

Preprint

View full text Add to dashboard Cite

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression. Tissue-specific factors linking stem-progenitor cell frequency to cancer risk and progression remain ill defined. Using a genetically engineered mouse model that promotes integrin mechanosignaling with syngeneic manipulations, spheroid models, and patient-derived xenografts we determined that a stiff extracellular matrix and high integrin mechanosignaling increase stem-progenitor cell frequency to enhance breast tumor risk and progression. Studies revealed that high integrin-mechanosignaling expands breast epithelial stem-progenitor cell number by potentiating progesterone receptor-dependent RANK signaling. Consistently, we observed that the stiff breast tissue from women with high mammographic density, who exhibit an increased lifetime risk for breast cancer, also have elevated RANK signaling and a high frequency of stem-progenitor epithelial cells. The findings link tissue fibrosis and integrin mechanosignaling to stem-progenitor cell frequency and causally implicate hormone signaling in this phenotype. Accordingly, inhibiting RANK signaling could temper the tumor promoting impact of fibrosis on breast cancer and reduce the elevated breast cancer risk exhibited by women with high mammographic density.SummaryElevated mechano-signaling and matrix stiffness promote progesterone and RANK mediated expansion of mammary progenitors and breast cancer risk and progression.

show abstract

FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

Cited by 22 publications

References 32 publications

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression

Contact Info

Product

Resources

About