Efficacy of PARP inhibitor Talazoparib on Invasive Lobular Carcinoma breast cancer models

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Presenter(s)

Jordan Swartz

Abstract or Description

Background: Anti-estrogens are a cornerstone of treatment for invasive lobular carcinoma (ILC) as nearly all ILC express estrogen receptor α (ER). However, anti-estrogen resistance remains a pervasive clinical problem. We previously linked ER activity and anti-estrogen resistance in ILC to ILC-specific activity of MDC1 (mediator of DNA damage checkpoint 1) as an ER co-regulator. We subsequently found that in ILC cells, canonical MDC1 functions in DNA repair may be compromised, manifesting as dysfunctional DNA double-strand break repair. ILC cells may be sensitive to PARP inhibitors (PARPi) as a mechanism to exploit this DNA repair dysfunction.

   Methods: ILC cell lines MDA-MB-134VI (MM134) and SUM44PE (44PE), and IDC cell lines MCF7 and T47D, were treated with FDA-approved PARPi talazoparib and/or anti-estrogens tamoxifen or fulvestrant. Aromatase inhibitors were modeled in ILC lines through short-term hormone-deprivation for 72 hours, followed by PARPi treatment. Proliferation and long-term survival was assessed by dsDNA quantification. Talazoparib response was examined in long-term estrogen-deprived (LTED) anti-estrogen resistant variants of MM134 and 44PE.

   Results: ILC cells were sensitive to single-agent talazoparib (IC50 = 38nM and 13nM in MM134 and 44PE, respectively), showing compromised long-term viability after drug wash-out. In contrast, T47D IDC cells were talazoparib-resistant (IC50 = 140nM); MCF7 showed initial sensitivity (IC50 = 20nM) but proliferated normally after drug wash-out. Combining anti-estrogens with talazoparib did not reduce ILC cell sensitivity to talazoparib, suggesting PARPi sensitivity in these cells is not explicitly linked to proliferation. LTED variants of 44PE and MM134 were sensitive and resistant to talazoparib, respectively, associated with differential activity of ER and MDC1 in these models.

   Conclusions: ILC cells are sensitive to PARP inhibition with talazoparib, potentially associated with an unappreciated DNA repair deficiency. Developing biomarkers of ER, MDC1, and DNA repair activity in ILC is critical toward understanding PARPi sensitivity in primary versus anti-estrogen resistant ILC. 

Mentor

Matthew Sikora