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Inhibiting p90 ribosomal S6 kinase (RSK)/Y-box binding protein-1 (YB-1) signaling is a novel targeted therapeutic strategy with the ability to overcome drug resistance in triple-negative breast cancer

University of British Columbia

Despite advances in treating breast cancer, disease recurrence rates remain high and secondary tumors are often refractory to chemotherapy. Currently, the treatment for triple-negative breast cancer (TNBC) relies upon conventional chemotherapeutics as no targeted therapies are available. Although these tumors initially respond well, they paradoxically have the highest relapse rates. Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor abundantly expressed in TNBC (~70% of patients) and associated with disease relapse. It is activated predominantly by phosphorylation via p90 ribosomal S6 kinase (RSK). Once activated YB-1 up-regulates the tumor-initiating cell (TIC) marker, CD44 and promotes drug resistance. These data suggest that blocking YB-1’s activation via RSK inhibition may suppress growth and attenuate the development of chemoresistance in TNBC. Through an unbiased, functional viability screen comparing breast cancer subtypes, we identified RSK2 as a novel target for TNBC. Pharmacological or siRNA inhibition of RSK2 blocks activation of YB-1, which subsequently decreases growth in TNBC cell lines and delays tumor initiation in immunocompromised mice. Contrary to most conventional chemotherapies, inhibiting RSK/YB-1 signaling eliminates the CD44⁺/CD24‾ cell fraction rather than enriching for it. In an effort to identify novel RSK inhibitors, we screened “off-patent” compounds and identified the flavonoid, luteolin, as a RSK inhibitor. We validated that luteolin inhibits RSK in cell-free assays and further demonstrated it blocks the RSK/YB-1/Notch4 signaling pathway. Luteolin phenotypically mirrored the effects of established RSK inhibitor, BI-D1870, and suppressed growth in TNBC (including CD44⁺/CD24‾-sorted cells) providing further support for the use of RSK inhibitors to treat this subtype. Finally, we demonstrate that cells that survive standard-of-care chemotherapeutics (paclitaxel and epirubicin) exhibit elevated RSK/YB-1 signaling. Inhibiting this pathway sensitizes TNBC to chemotherapy and reduces the residual cell burden. Importantly, RSK inhibition also demonstrates efficacy against a multidrug resistant cell line and primary, drug-refractory TNBC. When taken together, our data identify RSK as a promising target for the treatment of TNBC. RSK inhibition has the unique ability to eliminate CD44⁺/CD24‾cells and overcome broad-spectrum chemoresistance by blocking activation of YB-1 and as such holds potential to reduce relapse in this aggressive subtype.

Text

2013-06-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44616

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/