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RSK2: a promising therapeutic target for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characteristically associated with worse outcomes compared to other breast cancer subtypes. Cytotoxic chemotherapy combinations are the mainstay treatment for TNBC but paradoxically, following initial high rates of response to chemotherapy, many patients relapse within 2.5 years with refractory cancers. TNBC is a complex heterogeneous disease that can be further categorized into six subtypes, with a diverse number of genetic drivers that occur at low frequencies. The key to developing successful targeted therapies in the future may be in focusing on drug targets that transcend TNBC heterogeneity. In contrast to ER and HER2 breast cancer, in which kinase inhibitors such as palbociclib and trastuzumab, respectively, have had remarkable success in prolonging patient survival, no kinase inhibitor has been approved for the treatment of TNBC. However, the mitogen-activated protein kinase (MAPK) signaling pathway is highly activated in TNBC and promising data now indicate that p90 ribosomal S6 kinase 2 (RSK2), a downstream member of the MAPK signaling pathway, is a validated target for TNBC. The challenge ahead is to develop RSK inhibitors that have favorable pharmacokinetic properties, which will allow for their evaluation in clinical trials for patients with TNBC. TNBC is characterized histologically by a lack of ER, PR and HER2 expression and a high degree of heterogeneity with characteristics overlapping with basal-like breast cancer (BLBC) [1]. As such, TNBC and BLBC are often terms that are used interchangeably. The functional dependency of TNBC on RSK2 was discovered through unbiased kinome-wide screens across a heterogeneous panel of 34 breast cancer cell lines [2]. This siRNA screen of more than 700 genes identified RSK2 as the most important drug target for TNBC relative to other breast cancer subtypes. The critical role of RSK2 in TNBC was then validated through work by Stratford et al. (2012) in which siRNA was used to silence RSK2, leading to TNBC growth inhibition and apoptosis induction in vitro and tumor growth suppression in mice [3]. Pharmacological inhibition of RSK2 with the RSK inhibitor SL0101 further validated RSK2 as a TNBC target in xenografts in mice [4].The four RSK isoforms are highly conserved Ser/Thr downstream effector kinases in the MAPK cascade, that have important overlapping and unique roles in diverse cellular functions. In particular, RSK2 is a uniquely positioned kinase because it intersects two major signaling cascades: the MAPK pathway and the PI3K pathway (Figure 1). The reason that RSK2 is so important for TNBC may have to do with its ability to control transcription factors through Ser/Thr phosphorylation events. External growth factor ligands initiate signaling through ERK and PDK1 to activate RSK2 (Figure 1). Following activation, RSK2 phosphorylates a wide range of cytoplasmic and nuclear substrates with critical roles in cell proliferation and regulation, including the transcription/translation factor YB-1, which is associated with tumorigenesis and has a negative prognostic role in numerous cancers [5,6]. Activated RSK2 subsequently translocates into the nucleus and it is this nuclear localization of RSK2 hypothesized as the event that triggers the transformation of normal cells to malignant cells, specifically in breast cancer [7]. Indeed, a majority of TNBC patient tumors have activated nuclear RSK2. Thus, activated RSK2, visualized by immunohistochemical staining of nuclear RSK2 in tumor tissues, could be used as a novel biomarker for a TNBC companion diagnostic and phosphorylation of YB-1, a direct downstream substrate of RSK2, has utility as a biomarker of response to RSK therapy. Both MEK1/2 and RSK2 are associated with TNBC, but functionally they are very different kinases, with differences in their signaling processes (Table 1). Brough et al (2011) elegantly showed that TNBC is functionally dependent on RSK2, but not MEK, PI3K or PDK1 [2]. Disrupting this specific point in signal transduction also leads to cell death [3]. Interestingly, inhibition of MEK suppresses tumor growth in BLBC, but does not lead to apoptosis [8]. In addition, following treatment with MEK inhibitors, there is increased activation of Akt and compensatory stimulation of the PI3K/mTOR pathway in TNBC cells [4,9]. In contrast to MEK inhibitors, RSK2 inhibition does not affect phosphoAkt levels and RSK2 inhibition induces apoptosis in TNBC [8,10]. Typically, phosphoAkt, PTEN and K-Ras are used as pharmacodynamic biomarkers of response to MEK1/2 inhibitors, whereas phosphoYB-1 (a direct substrate) is used tomonitor RSK2 inhibition. Based on this data, it is clear that RSK2 has distinct advantages over MEK as a promising molecular target for TNBC therapy (Table 1). RSK inhibitors are thus positioned to short circuit TNBC cell signaling, that ultimately leads to cancer cell death.