TNBC occurs in approximately 15 to 20% of patients with breast cancer and is associated with an unfavorable prognosis [
10]. Although patients with TNBC who achieve complete pathological response have better survival [
23], patients who have significant residual disease are at high risk of relapse and have limited options upon recurrence. Therefore there is a great need for superior therapy options for TNBC. Here we showed the antitumor efficacy of selinexor, as a novel approach for TNBC therapy.
XPO1 compartmentalizes tumor suppressors and cell cycle regulators, which are dependent on location to exert their apoptotic/proliferative functions [
24]. Many of these have been linked to the elusive molecular network in TNBC [
11], providing a rationale for exploring XPO1 inhibition as a potential target for cancer therapy. Our findings have established the antitumor efficacy of selinexor, a selective inhibitor of nuclear export, on breast cancer. We have shown that selinexor effectively inhibits cell proliferation and cell growth both in vitro and in vivo at biologically relevant drug concentrations
. Our experiments suggest that there is enhanced sensitivity of TNBC cell lines to selinexor compared with ER+ cells. Treatment with selinexor as a single agent resulted in enhanced tumor growth inhibition in four of five TNBC PDX models in vivo. We also demonstrated that treatment with selinexor induced apoptosis. Concordantly, treatment with selinexor decreased levels of survivin, XIAP, and β-catenin. Furthermore, while survivin has been previously reported as a possible explanation for the mechanism of action of selinexor [
3,
25], by testing a wide array of breast cancer cell lines in this study, we have shown that selinexor decreases XPO1 expression and survivin expression not only in selinexor-sensitive cell lines but also in selinexor-resistant lines. We have also shown that selinexor is effective independent of PTEN, PIK3CA, TP53, or Ras/Ras status. Although we did see greater sensitivity in TNBC cell lines compared to other subtypes, we have not tested the sensitivity of ER+ and HER+ cancers in vivo, and we have not determined the mechanism behind the differential sensitivity between subtypes in vitro. Further studies are needed to identify pharmacodynamic markers of response and mechanisms of intrinsic resistance. The inherent complexity of the mechanism behind XPO1 inhibition involves the ability of XPO1 to interact with several different tumor suppressors and cell cycle regulators, therefore potentially targeting multiple pathways. One of the most common examples is the role of XPO1 inhibition leading to the accumulation of TP53 in the nucleus, an exciting finding of a possible mechanism explaining its anti-proliferative effects in leukemia, lymphoma, prostate cancer, melanoma, and hepatocellular carcinoma [
26‐
28]. In our study, however, most cell lines tested were
TP53 mutant yet differed in their selinexor sensitivity. Thus, XPO1 inhibition is effective independent of the TP53 status as we have shown here, consistent with what has been previously shown for sarcoma, non-small cell lung cancer, multiple myeloma, and mesothelioma [
29‐
32].
Selinexor also had enhanced efficacy when combined with standard chemotherapy agents. Four different TNBC cell lines showed notable synergy in vitro, in particular with doxorubicin and paclitaxel (median CI values of 0.6 and 0.5, respectively), agents used commonly in the neoadjuvant or adjuvant treatment of TNBC, and to some extent with carboplatin and eribulin (median CI values of 0.8 and 0.7, respectively). At the same time, the combination of selinexor with paclitaxel enhanced apoptosis. Further, selinexor showed enhanced antitumor activity in vivo when combined with paclitaxel and eribulin, with T/C ratios <40% in three different TNBC PDX models.