FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4
Simoes, Bruno M
Clarke, Robert B
AffiliationCentre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
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AbstractBACKGROUND: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. METHODS: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. RESULTS: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n???3, p?<?0.05) and invasion (n???3, p?<?0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p?<?0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n???3, p?<?0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p?<?0.05) or 21?days (p?<?0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. CONCLUSION: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need. KEYWORDS: AD-01; ALM201; Breast cancer stem cells; DLL4; Endocrine therapy; Estrogen receptor; FKBPL; Letrozole; Metastasis; Notch4; Tamoxifen; Triple negative breast cancer
CitationMcClements L, Annett S, Yakkundi A, O'Rourke M, Valentine A, Moustafa N, et al. FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer. 2019 Apr 11;19(1):351.
- Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway.
- Authors: McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R, Donley C, Kissenpfennig A, McIntosh S, McCarthy HO, O'Neill E, Clarke RB, Robson T
- Issue date: 2013 Jul 15
- Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
- Authors: Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB
- Issue date: 2015 Sep 29
- FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.
- Authors: Annett S, Moore G, Short A, Marshall A, McCrudden C, Yakkundi A, Das S, McCluggage WG, Nelson L, Harley I, Moustafa N, Kennedy CJ, deFazio A, Brand A, Sharma R, Brennan D, O'Toole S, O'Leary J, Bates M, O'Riain C, O'Connor D, Furlong F, McCarthy H, Kissenpfennig A, McClements L, Robson T
- Issue date: 2020 Feb
- Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen.
- Authors: Donley C, McClelland K, McKeen HD, Nelson L, Yakkundi A, Jithesh PV, Burrows J, McClements L, Valentine A, Prise KM, McCarthy HO, Robson T
- Issue date: 2014 Jun 26
- PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer.
- Authors: Santiago-Gómez A, Kedward T, Simões BM, Dragoni I, NicAmhlaoibh R, Trivier E, Sabin V, Gee JM, Sims AH, Howell SJ, Clarke RB
- Issue date: 2019 Aug 28