Inhibition of FAK kinase activity preferentially targets cancer stem cells.

Vihren N Kolev,Christian M Vidal,Qunli Xu,Max S Wicha,Irina M Shapiro,David T Weaver,Sean P Mcdermott,Winnie F Tam,Jonathan A Pachter,Quentin G Wright

doi:10.18632/oncotarget.18517

Vihren N Kolev, Christian M Vidal + Show 8 more

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https://doi.org/10.18632/oncotarget.18517

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Abstract

Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo. Oral administration of VS-4718 or VS-6063 to mice bearing xenograft models of triple-negative breast cancer (TNBC) significantly reduced the proportion of CSCs in the tumors, as evidenced by a reduced tumor-initiating capability upon re-implantation in limiting dilutions of cells prepared from these tumors. In contrast, the cytotoxic chemotherapeutic agents, paclitaxel and carboplatin, enriched for CSCs, consistent with previous reports that these cytotoxic agents preferentially target non-CSCs. Importantly, VS-4718 and VS-6063 attenuated the chemotherapy-induced enrichment of CSCs in vitro and delayed tumor regrowth following cessation of chemotherapy. An intriguing crosstalk between FAK and the Wnt/β-catenin pathway was revealed wherein FAK inhibition blocks β-catenin activation by reducing tyrosine 654 phosphorylation of β-catenin. Furthermore, a constitutively active mutant form of β-catenin reversed the preferential targeting of CSCs by FAK inhibition, suggesting that this targeting is mediated, at least in part, through attenuating β-catenin activation. The preferential targeting of cancer stem cells by FAK inhibitors provides a rationale for the clinical development of FAK inhibitors aimed to increase durable responses for cancer patients.

Highlights

Research over the last decade has led to the hypothesis that individual tumors contain diverse populations of neoplastic cells, including a minor subpopulation of cancer stem cells (CSCs) or tumorinitiating cells (TIC), having the capability for tumorinitiation, self-renewal, and potential to differentiate into the heterogeneous tumor cell populations present within tumors [1]
focal adhesion kinase (FAK) kinase function is important for CSC in basal-like triple-negative breast cancer (TNBC) and high grade ductal carcinoma in situ (DCIS), while a kinase-independent function may be important for maintenance of CSC in claudin-low breast cancers [27, 42], a subset of breast cancer accounting for about 7-14% of TNBC [43]
In vivo, and ex vivo treatment of breast cancer cell lines and patient samples with either VS-4718 or VS-6063 led to preferential reduction of CSC subpopulations as demonstrated by 1) decrease of the proportion of Aldefluor+ and Side Population (SP) cells, 2) attenuation of tumorsphere-forming efficiency, and 3) reduction of tumor-initiating capacity as measured by re-implantation in limiting dilution assays

Summary

Introduction

Research over the last decade has led to the hypothesis that individual tumors contain diverse populations of neoplastic cells, including a minor subpopulation of cancer stem cells (CSCs) or tumorinitiating cells (TIC), having the capability for tumorinitiation, self-renewal, and potential to differentiate into the heterogeneous tumor cell populations present within tumors [1]. Most current anticancer therapies target the bulk populations of cancer cells within tumors Because they are less effective against CSCs, some CSCs may survive the initially employed therapeutic agents and generate tumor regrowth at primary and metastatic sites. Similar observations have been published by multiple groups and extended to other cancers including ovarian and non-small cell lung cancers [5,6,7,8,9,10] These studies provide clinical proof-of-concept for the importance of CSCs in patient prognosis, and suggest that combination of CSC-targeting agents with conventional bulk tumor cell-targeting therapy may be critical for meaningful improvement of long term survival of patients with cancer [11, 12]. Clinical trials with CSC-targeting agents have been prompted by these recent advances [13]

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