Pmd-026, A First In Class Oral Rsk Inhibitor, Demonstrates Synergy When Combined With Standard Of Care In Breast Cancer Tumor Models.

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 and PDK-1 pathways, which regulate substrates involved in cancer cell proliferation and drug resistance. Specifically, RSK2 has been identified as a major driver in breast cancer (BC). In preclinical studies and a Phase I clinical trial in metastatic BC, PMD-026 demonstrated a good safety profile, making it an attractive candidate for combinations with standard of care therapies. Here in we show that RSK2 is activated in 87% of triple negative breast cancer (TNBC), as well as in other subtypes (80% of ER+/PR+ and 81% of HER2+). In a screen of 28 BC cell lines across a broad mutational spectrum, PMD-026 induced apoptosis in most of the models. Next, to determine the role of PMD-026 in the context of conventional BC treatment, we combined it with standard of care chemotherapies fulvestrant, paclitaxel, or doxorubicin, in vitro and in vivo. PMD-026 synergized with fulvestrant, with combination drug index (CDI) values ranging from 0.73 - 0.92 in the HR+ cell line MCF-7. Likewise, PMD-026 synergized with paclitaxel and doxorubicin in TNBC cell lines with CDI values ranging from 0.40 - 0.84 and 0.58 - 0.92 for paclitaxel and doxorubicin, respectively. Consistent with in vitro screening data, PMD-026 synergized with paclitaxel in vivo in the SUM149PT TNBC xenograft model after 38 days of treatment. The combination inhibited tumor growth by 66% (P < 0.0001), whereas paclitaxel and PMD-026 as single agents inhibited tumor growth by 22% (P = 0.3051) and 41% (P = 0.0041), respectively. The synergy of this combination was further supported by a CDI value of 0.75. Treatment among the groups was well tolerated with no changes in body weight observed. Similarly, the combination of PMD-026 and paclitaxel was synergistic in SUM149PT(48 days, CDI: 0.78) and MDA-MB-231 (28 days, CDI: 0.66) xenografts and additive in a PDx model of metastatic TNBC (18 days, CDI: 0.96), resulting in improved survival. To address the safety of combining PMD-026 and paclitaxel, drug-drug interactions (DDI) were assessed. In cytochrome P450-mediated in vitro metabolism assays, PMD-026 showed weak inhibition of Cyp2C8 and Cyp3A4, the main enzymes responsible for paclitaxel metabolism. To understand whether PMD-026 might alter the metabolism of paclitaxel, this potential DDI was assessed in vivo. Pharmacokinetic analysis of PMD-026 (7 days repeat dosing) combined with paclitaxel (8 mg/kg IV dose Day 1 and Day 7) was evaluated in CD-1 mice, however, PMD-026 did not change the absorption, distribution, or blood levels of paclitaxel. Together, these data support adding PMD-026 to standard of care therapies in breast cancer, as they have demonstrated synergy. In particular, PMD-026 is synergistic with paclitaxel in multiple TNBC models, in which it improves efficacy without added toxicity. Citation Format: Aarthi Jayanthan, My-my Huynh, Jangsoon Lee, Gerrit Los, Lambert Yue, Mary Rose Pambid, Naoto T. Ueno, Sandra E. Dunn. PMD-026, a first in class oral RSK inhibitor, demonstrates synergy when combined with standard of care in breast cancer tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1038.