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

Simon Timbrell; Hosam Aglan; Angela Cramer; Philip Foden; David Weaver; Jonathan Pachter; Aoife Kilgallon; Robert Clarke; Gillian Farnie; Nigel Bundred

doi:10.1038/s41523-021-00263-3

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

Simon Timbrell, Hosam Aglan, Angela Cramer, Philip Foden, David Weaver, Jonathan Pachter, Aoife Kilgallon, Robert Clarke, Gillian Farnie, Nigel Bundred

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Cancer Stem-like Cells (CSC) contribute to therapy resistance and recurrence. Focal Adhesion Kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies.
FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and Paclitaxel reduced self-renewal in triple negative cell lines.
An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population.
Combined FAK and Paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative Patient Derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.

Original language	English
Article number	7
Pages (from-to)	65
Journal	NPJ Breast Cancer
Early online date	28 May 2021
DOIs	https://doi.org/10.1038/s41523-021-00263-3
Publication status	E-pub ahead of print - 28 May 2021

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title = "FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity",

abstract = "Cancer Stem-like Cells (CSC) contribute to therapy resistance and recurrence. Focal Adhesion Kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies.FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and Paclitaxel reduced self-renewal in triple negative cell lines.An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population.Combined FAK and Paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative Patient Derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.",

author = "Simon Timbrell and Hosam Aglan and Angela Cramer and Philip Foden and David Weaver and Jonathan Pachter and Aoife Kilgallon and Robert Clarke and Gillian Farnie and Nigel Bundred",

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doi = "10.1038/s41523-021-00263-3",

language = "English",

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T1 - FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

AU - Timbrell, Simon

AU - Aglan, Hosam

AU - Cramer, Angela

AU - Foden, Philip

AU - Weaver, David

AU - Pachter, Jonathan

AU - Kilgallon, Aoife

AU - Clarke, Robert

AU - Farnie, Gillian

AU - Bundred, Nigel

PY - 2021/5/28

Y1 - 2021/5/28

N2 - Cancer Stem-like Cells (CSC) contribute to therapy resistance and recurrence. Focal Adhesion Kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies.FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and Paclitaxel reduced self-renewal in triple negative cell lines.An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population.Combined FAK and Paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative Patient Derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.

AB - Cancer Stem-like Cells (CSC) contribute to therapy resistance and recurrence. Focal Adhesion Kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies.FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and Paclitaxel reduced self-renewal in triple negative cell lines.An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population.Combined FAK and Paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative Patient Derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.

U2 - 10.1038/s41523-021-00263-3

DO - 10.1038/s41523-021-00263-3

M3 - Article

SN - 2374-4677

SP - 65

JO - NPJ Breast Cancer

JF - NPJ Breast Cancer

M1 - 7

ER -

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

Abstract

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