BET Inhibition: An effective therapeutic strategy for lobular breast cancer?
Invasive lobular carcinoma (ILC) is a subtype of breast cancer that arises from the milk-producing lobules of the breast. It accounts for 10% of all breast cancers and is often oestrogen receptor (ER) positive.
This subtype of breast cancer is underrepresented in scientific studies and tends to have more late recurrence than invasive ductal carcinoma (IDC), the most frequently encountered form of breast cancer. ILC is also considered chemo-resistant; there remains uncertainty as to whether these patients benefit from adjuvant chemotherapy when anti-endocrine therapy fails.
In the study available here, Dr Tríona Ní Chonghaile from the Department of Physiology and Medical Physics in RCSI, alongside Dr Darran O’Connor, Prof. William Gallagher and her team, attempt to identify novel therapeutic strategies for ILC in the resistant setting, with the results pointing towards a combination of BET inhibitors and FGFR1 inhibitors as a potential treatment.
The RCSI team investigated the sensitivity of ILC to BET inhibition with JQ1 — a potent inhibitor of the BET family of bromodomain proteins — in 2D and 3D models, attempting to overcome the resistance seen in ILC cell lines.
The 3D cultures allow cells to experience a complex, three-dimensional environment and exposure to circulating molecules, neighbouring cells and the extracellular matrix that more closely resembles in-vivo conditions. This is in comparison to a 2D model where cells are cultured in a single layer on collagen-coated glass.
JQ1-induced growth arrest in multiple different cellular models of ILC used in the study; however, two of the cell lines were intrinsically resistant to JQ1-induced apoptosis. Dynamic BH3 profiling, a functional measure of death signalling that predicts the response to targeted agents in-vitro and in-vivo, was carried out on these cell lines and determined that JQ1 induced dependence on anti-apoptotic proteins.
RNA sequencing of the resistant cell lines demonstrated evidence of FGFR1 rewiring and JQ1-resistant cell lines revealed an increase in the mRNA and protein level in FGFR1 in both ILC and IDC cell lines.
The authors illustrated how the combination of JQ1 and the FGRR1 inhibitor, PD173074, were effective at inhibiting the growth of ILC in long-term 3D cultures. The authors then went on to use copy number alteration and RNA sequence data from 61 patients with ILC from the RATHER cohort.
They found that 20% of patients in this cohort had FGFR1 amplification.
They also found that high expression of BRD3 was associated with poor outcomes. Using the METABRIC ILC cohort, the authors determined that high BRD3 mRNA expression was associated with poor disease-specific survival in patients with OR+ ILC.
In conclusion, the data presented by the authors support the hypothesis that a combination of BET inhibitors and FGFR1 inhibitors may be a useful therapeutic strategy for patients with recurrent ILC going forward.
Journal Article Information:
BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
Clin Cancer Res. 2019 Dec 1;25(23):7139–7150