Pilot Project – RSK Inhibition as a Targeted Therapy for Basal-Like Breast Cancer
Title: RSK Inhibition as a Targeted Therapy for Basal-Like Breast Cancer
Project Leads:
- Deborah Ann Lannigan, PhD, Vanderbilt University
- Amos Sakwe, PhD – Meharry Medical College
- Venkataswarup Tiriveedhi, MD, PhD – Tennessee State University
Project Summary:
There is an ongoing need for targeted therapies for the treatment of basal-like breast cancer (BLBC), which comprises ~ 80% of triple-negative breast cancer (TNBC). The Serine/Threonine protein kinase family, RSK, are downstream MEK1/2-ERK1/2 effectors, a pathway that is active in the majority of BLBCs. There are four members of the RSK family, with RSK1/2 associated with transformation and metastasis and RSK3/4 implicated as tumor suppressors (Ludwik and Lannigan, 2016). My laboratory discovered the first RSK-specific inhibitor and using this inhibitor we were the first to demonstrate the importance of RSK in cancer (Clark et al., 2005; Smith et al., 2005). The parent compound, SL0101, was synthesized and subjected to structure-activity-relationship (SAR) studies to identify an analogue, C5”-n-propyl cyclitol SL0101 (1b). This analogue (1b) is specific for RSK1/2 and was demonstrated to be on-target in vivo (Ludwik et al., 2016). The compound (1b) reduced BLBC metastatic burden in a xenograft model. Based on our work and others a pan-RSK inhibitor, PMD-026, has now entered a phase 1/1b clinical trial for metastatic breast cancer (NCT04115306). There are no published data with PMD-026 in a pre-clinical metastatic model. However, in the clinical trial PMD-026 extended progression free survival in heavily pre-treated patients with metastatic breast cancer (Beeram et al., 2021). PMD-026 demonstrates a good safety profile in contrast to MEK1/2 and ERK1/2 inhibitors. Based on these encouraging results an expansion of the clinical trial is planned, but this expansion raises a major concern as the importance of RSK in tumor immunology has not been well examined. In fact, the only published study exploring RSK inhibition in a tumor model using an immune competent mouse demonstrated that knockout of RSK2 increased metastasis in a colon cancer model (Yao et al., 2017). However, there is in vitro evidence in melanoma that PMD-026 may improve the efficacy of immune-based therapies (Kosnopfel et al., 2023). Therefore, as more patients are expected to enter clinical trials using PMD-026 it is critical to identify the contributions of RSK to the tumor immune response.
Additionally, it is important to evaluate whether using a pan RSK inhibitor is the optimum therapeutic option given the observations for RSK3/4. The goals of this pilot proposal are to determine the effects of a pan-RSK inhibitor, PMD-026, compared to a RSK1/2-specific inhibitor (1b) in the context of BLBC with a focus on RSK in the tumor immune response.
Specific Aims:
1) Identify whether RSK contributes to the immune response in basal-like breast cancer. A syngeneic basal-like mammary cancer line, PY8119, will be engineered to express luciferase and be introduced by intra-cardiac injection to induce metastasis. The compounds (1b) and PMD-026 which demonstrate in vivo efficacy, are available. These structurally divergent compounds have been synthesized in sufficient quantities for this project by the Chemical Synthesis Core. Metastasis will be monitored. Immune and cytokine profiling will be performed on tumor-bearing mice in the presence and absence of a RSK inhibitor. Tumor tissue will be analyzed for tumor immune response and on-target RSK inhibition.
2) Evaluate the efficacy of a pan RSK versus a RSK1/2 specific inhibitor using human basal-like breast cancer organoid models. Thirty-one cryopreserved TNBC tumors (~30% from patients of African ancestry) are available. Organoids from this collection that are BLBC and have high RSK activity will be generated. The organoids will be analyzed to ensure their fidelity to the starting tissue and on-target RSK inhibition, tumor immune response, proliferation and apoptosis will be measured.