Synergy of BCL-2 and MEK/HDAC inhibition in IBC and non-IBC models: Potential for a first IBC specific therapy

Background: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer characterized by rapid progression. Despite its unique clinical presentation, there are no IBC specific therapies. IBC growth is not faster than non-IBC, so evasion of apoptosis, mediated by the B-cell lymphoma 2 (BCL-2) family, is hypothesized to be a major mechanism for IBC persistence. Aberrant BCL-2 expression favors tumor survival. Although BCL-2 inhibition can restore apoptotic activity, single-agent activity remains limited by compensatory signaling. Our initial high-throughput screen indicated that certain drug classes including: HSP90, BCL-2, MEK, and HDAC inhibitors showed a trend toward greater activity in IBC compared to non-IBC models. This led us to explore rational combination strategies across our panel of IBC and non-IBC breast cancer models. Methods: We screened eight breast cancer cell lines (3 IBC: SUM-149, SUM-190, IBC-1; and 5 non-IBC: MDA-MB-231, JIMT-1-GFP, BT-474, MUM51, HCC1143) with a library of more than 1,200 compounds to identify drug classes with increased sensitivity in IBC relative to non-IBC. This initial screen identified HSP90, BCL-2, MEK, and HDAC inhibitors as classes of interest. We then performed follow-up combination screens using Pimitespib (HSP90 inhibitor) and Navitoclax (BCL-2 inhibitor), the top hits within their respective classes, testing them against the same 1,200+ compound library to identify synergistic partners. In parallel, we rationally combined inhibitors of multiple active pathways (e.g., BCL-2 + MEK or BCL-2 + HDAC), which have shown synergy in other cancers, to evaluate additional synergistic interactions. Combination effects were assessed using the Chou-Talalay method (CI < 1 indicating synergy). Results: Our high-throughput screen identified HSP90, BCL-2, MEK, and HDAC inhibitors as more sensitive in IBC relative to non-IBC. Secondary screens pairing Pimitespib (HSP90 inhibitor) or Navitoclax (BCL-2 inhibitor) with the same compound library identified synergistic partners. Pimitespib synergized with taxanes and PI3K/MAPK inhibitors in select lines such as MDA-231 and BT474, whereas Navitoclax consistently showed strong synergy with MEK and HDAC inhibitors in IBC models. Distinct subtype-dependent trends emerged: synergy between BCL-2 and MEK inhibition was strongest in IBC, while BCL-2 and HDAC synergy predominated in non-IBC lines. Conclusions: This study shows for the first time a trend towards IBC-specific synergistic drug interactions. These findings suggest potential mechanistic differences in apoptotic regulation and may guide rational development of targeted combination therapies for IBC. Future studies will assess whether these in vitro synergy trends translate into subtype-specific therapeutic responses in vivo. AI disclosure: AI was used only for language editing; content was verified by the authors.