2. Academic Validation
  3. BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer

BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer

  • Clin Cancer Res. 2019 Dec 1;25(23):7139-7150. doi: 10.1158/1078-0432.CCR-19-0713.
Louise Walsh  # 1,  Kathryn E Haley  # 2,  Bruce Moran 3,  Brian Mooney 1,  Finbarr Tarrant 3,  Stephen F Madden 4,  Alessandra Di Grande 2,  Yue Fan 3,  Sudipto Das 1,  Oscar M Rueda 5,  Catríona M Dowling 2,  Damir Varešlija 6,  Suet-Feung Chin 5,  Sabine Linn 7,  Leonie S Young 6,  Karin Jirström 8,  John P Crown 9,  Rene Bernards 10,  Carlos Caldas 11,  William M Gallagher  # 3,  Darran P O'Connor  # 12,  Tríona Ní Chonghaile  # 2
Affiliations

Affiliations

  • 1 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 2 Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 3 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
  • 4 Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 5 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
  • 6 Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 7 Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 8 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 9 Department of Medical Oncology, Dublin, Ireland.
  • 10 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 11 Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, England.
  • 12 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. darranoconnor@rcsi.com.
  • # Contributed equally.
PMID: 31409615 DOI: 10.1158/1078-0432.CCR-19-0713
Abstract

Purpose: Invasive lobular carcinoma (ILC) is a subtype of breast Cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast Cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast Cancer but they have not yet been assessed in ILC.

Experimental design: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced Apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.

Results: Certain ILC cell lines were sensitive to JQ1, while Others were intrinsically resistant to JQ1-induced Apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing Fibroblast Growth Factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.

Conclusions: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.

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