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Updated: Mar 16, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer
Katarzyna A Ludwik1, J Preston Campbell1, Mingzong Li2
1Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee.
Abstract:
Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo Mol Cancer Ther; 15(11); 2598-608. ©2016 AACR.
Insights
Targeting p90 ribosomal S6 kinase (RSK) with a novel inhibitor effectively reduced metastasis in triple-negative breast cancer (TNBC) models. This approach offers a promising new therapeutic strategy for this aggressive form of breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic breast cancer remains incurable, necessitating novel therapeutic targets.
- Triple-negative breast cancer (TNBC) is characterized by frequent metastasis.
- Activated p90 ribosomal S6 kinase (RSK) is prevalent in TNBC.
Purpose of the Study:
- To investigate the role of RSK kinases in TNBC metastasis.
- To evaluate the efficacy of a novel RSK inhibitor (SL0101 analogue) in preclinical TNBC models.
Main Methods:
- Pharmacologic and genetic inhibition of RSK1/2 in TNBC.
- Kinase profiling to confirm RSK1/2 as primary targets of the novel inhibitor.
- In vivo studies assessing the inhibitor's effect on metastatic foci establishment.
- Evaluation of AKT pathway activation following RSK1/2 inhibition.
Main Results:
- Direct inhibition of RSK1/2 significantly contributed to reducing TNBC metastasis in vivo.
- The novel SL0101 analogue selectively targeted RSK1 and RSK2.
- The RSK inhibitor demonstrated efficacy comparable to the MEK inhibitor trametinib in reducing metastasis.
- RSK1/2 inhibition did not lead to AKT activation, avoiding a known limitation of MEK inhibitors.
Conclusions:
- RSK is a critical driver of the metastatic process in TNBC.
- The novel SL0101 analogue targeting RSK1/2 provides preclinical proof-of-concept for TNBC therapy.
- Targeting RSK represents a potential therapeutic strategy to overcome limitations of current treatments.
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