Abstract 5378: PMD-026, a first in class oral RSK inhibitor, demonstrates activity against hormone receptor positive breast cancer with acquired CDK4/6 inhibitor resistance

Abstract

Abstract PMD-026 is a first in class, reversible, oral small molecule inhibitor of p90 ribosomal S6 kinase (RSK), a kinase family activated by the MAPK, PDK-1 and PI3K pathways, which regulate substrates involved in cancer cell proliferation and drug resistance. Specifically, both MAPK and PI3K pathways are implicated in resistance to standard of care (SOC) CDK4/6 inhibitors in hormone receptor positive (HR+) breast cancer (BC). RSK2 is expressed in 80% of HR+ BC, therefore we hypothesized that disrupting these critical pathways with PMD-026 could overcome resistance to CDK4/6 inhibitors through cell growth inhibition, apoptosis induction and downstream target inhibition alone and in combination with SOC SERD fulvestrant. In preclinical studies and a Phase I/Ib clinical trial in metastatic BC, PMD-026 demonstrated a good safety profile, making it an ideal candidate for the CDK4/6 inhibitor resistant HR+ BC population. Here in we demonstrate that PMD-026 inhibits growth of HR+ BC cell lines MCF-7 and T47D in vitro at IC50 values ranging from 3.7 to 10.1 µM, resulting in dephosphorylation of the RSK downstream effector YB-1 and induction of apoptosis through PARP cleavage. Comparatively, the MAPK pathway remains active in the presence of fulvestrant, as indicated by the expression of pYB-1. We determined that PMD-026 synergizes with fulvestrant in the MCF-7 model in vitro with a combined drug index (CDI) of 0.73 to 0.92. The next step was to determine if this combination is effective in cells resistant to CDK4/6 inhibitors. For that purpose, MCF-7 and T47D cells were treated with increasing concentrations of the CDK4/6 inhibitor palbociclib (Ibrance) up to 2 µM for several months. The generated Ibrance resistant cell lines (MCF-7-IBR, T47D-IBR) are insensitive to Ibrance up to 2 µM, but their parental counterparts have IC50 values ranging from 0.05 to 0.15 µM. In addition, cross-resistance to an additional CDK4/6 inhibitor, abemaciclib (Verzenio), was observed in the resistant cell lines, but the parental lines remained sensitive at IC50 values ranging from 0.15 to 0.25 µM. Most importantly, both parental and resistant cell lines remained sensitive to PMD-026 at similar IC50 values, indicating that CDK4/6 inhibitor resistance does not affect PMD-026 sensitivity. PMD-026 was then tested in combination with fulvestrant in anchorage independent conditions in the MCF-7-IBR cells. It was determined that this combination was highly synergistic with CDI ranging from 0.55 to 0.79. Together, these data support the application of PMD-026 and fulvestrant as a novel method to stop the growth of HR+ BC with acquired resistance to CDK4/6 inhibitors. Additionally, given that the MAPK pathway is upregulated in response to PI3K inhibition, the PMD-026 and fulvestrant combination is a potential alternative treatment for HR+ BC patients. Citation Format: Aarthi Jayanthan, Lambert Yue, My-my Huynh, Gerrit Los, Sandra E. Dunn. PMD-026, a first in class oral RSK inhibitor, demonstrates activity against hormone receptor positive breast cancer with acquired CDK4/6 inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5378.