Targeting DNA Repair Dysfunction in Lobular Breast Cancer by PARP Inhibition

Invasive Lobular Carcinoma (ILC) is an estrogen receptor alpha-positive (ER+) subtype of breast cancer that relies heavily on estrogen signaling. As part of this reliance, we identified a novel cross-talk in ILC cells between ER and DNA repair machinery that facilitates ER function. In this context, we find that cells are potentially reliant on poly(ADP-ribose) polymerase (PARP)-mediated repair to maintain genome integrity, despite ILC cells not otherwise presenting “BRCA-like” features typically associated with PARP inhibitor (PARPi) sensitivity. In fact, we found that ILC cells in vitro are hyper sensitive to the PARPi talazoparib (Tala) versus other breast cancer cell lines. Based on this, we used ILC in vivo models to test Tala efficacy alone and in combination with anti-estrogen treatments.

We tested Tala (0.33mg/kg p.o. daily, 5 days/week), estrogen-deprivation (to mimic aromatase inhibition, AI), Fulvestrant (an ER antagonist, 5mg/kg, s.c. weekly) and combinations in ILC cell line xenografts (MM134 and 44PE) and a patient-derived xenograft (HCI-013) in mice. Cells were injected bilaterally to the #4 mammary fat pads, tumors developed with estrogen supplementation in the drinking water, which was maintained except if the mice were on an “AI” treatment. Mice were treated for 6 weeks (10 weeks for the PDX), and followed until they reached human endpoints.

Across all models, treatment differences particularly emerged in the post-treatment phase, where the Tala+AI caused a durable delay in tumor outgrowth. In the MM134 xenografts, talazoparib alone suppressed tumor growth vs control (ANOVA p=0.0016). Tala+AI showed even better suppression compared to all single-agent treatments (ANOVA p=0.0006 vs talazoparib; p=0.0037 vs AI). Similarly, in 44PE xenografts, Tala+AI demonstrated the best tumor growth suppression (ANOVA, p<0.0001 vs AI). Preliminary data from PDx HCI-013 indicate a similar trend on treatment, with Tala+AI showing better tumor suppression than AI.

These findings show a potential synergy between talazoparib and aromatase inhibition in treating ILC. Combination therapy effectively suppresses tumor growth on treatment and delays the tumor re-growth post-treatment. This indicates that ILC is unexpectedly sensitive to PARP inhibition, suggesting the need to deepen our understanding of ER cross-talk with DNA repair mechanisms in ILC. Testing in additional in vivo models is ongoing toward supporting clinical translation.

Date of Presentation October 17, 2024